4-Benzoylindan-1-carboxamide and derivatives thereof

ABSTRACT

Compounds of the formula: ##STR1## wherein R 1  is an aryl group which may be substituted, R 2  is hydrogen or a lower alkyl group having 1 to 4 carbon atoms and n is 1 or 2, or derivatives at the carboxyl function thereof, are useful as medicines such as antipyretics, analgesics and anti-inflammatory agents.

This is a division of application Ser. No. 496,855, filed Aug. 12, 1974now U.S. Pat. No. 3,953,500.

The present invention relates to a novel compound of the followinggeneral formula (I): ##STR2## wherein R¹ is an aryl group which may besubstituted, R² is hydrogen or a lower alkyl group having 1 to 4 carbonatoms and n is 1 or 2, or a derivative at the carboxyl function thereof.

The present inventors have made extensive study about a series of indanderivatives and 1,2,3,4-tetrahydronaphthalene derivatives and succeededin synthesizing the novel compound of the above formula (I) and aderivative at the carboxyl function thereof, and have found that theabove compounds have remarkable antipyretic, analgesic andanti-inflammatory effects.

The present invention has been accomplished on the basis of thisfinding.

The principal object of this invention is to provide novel compounds ofthe formula (I) useful as medicines such as antipyretics, analgesics andanti-inflammatory agents.

Another object of this invention is to provide methods for theproduction of these novel compounds.

Further objects will be made apparent from the description and claimshereinafter given.

The derivatives at the carboxyl function of compound (I) may be thecorresponding ester, acid amide or salt. The esters include alkyl esterswhose alkyl moieties are, for example, methyl, ethyl, propyl,iso-propyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, n-pentyl,n-hexyl, etc., aryl esters such as phenyl ester, etc., aralkyl esterssuch as benzyl ester, etc.

The acid amides include not only those which carboxyl moieties can berepresented by --CONH₂ but also the hydroxamic acids represented by--CONHOH, the hydrazides represented by --CONHNH₂, the N-mono- ordi-substituted acid amides corresponding to such organic amines as mono-or di-lower alkylamines of about 1 to about 3 carbon atoms whose alkylmoieties may be substituted by hydroxyl (for example, ethanolamine,diethanolamine, methylamine, ethylamine, dimethylamine, diethylamine,propylamine, etc.), arylamines (for example, aniline, methylaniline,etc.), five- to six-membered cyclic amines containing 1 to 2 nitrogenatoms (for example, morpholine, pyrrolidine, piperidine, piperazine,N-substituted piperazine, etc.), N-aralkyl-substituted amines (forexample, benzylamine, alpha-methylbenzylamine, phenethylamine, etc.),alkyl-substituted or aryl-substituted hydrazines (for example, methylhydrazine, dimethyl hydrazine, phenyl hydrazine, etc.) and the like. Asthe salts, there may be mentioned, among others, the salts with alkalimetals (for example, sodium, potassium, etc.), alkaline earth metals(for example, calcium, magnesium, etc.) and metals such as aluminum, aswell as the ammonium salts and the salts with the organic amines such asthose similar to organic amines exemplified as those of the residue foracid amides.

The aryl group represented by R¹ includes such species as phenyl,naphthyl, etc., each of which may be further substituted. Thesubstituent or substituents on the aryl group may be any of lower alkylshaving 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl,n-butyl, isobutyl, tert.-butyl, etc., lower alkoxy having 1 to 4 carbonatoms such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy,tert.-butoxy, etc., halogens such as chlorine, bromine, fluorine etc.,mono- or di-alkylamino having 1 to 3 carbon atoms such asN,N-dimethylamino, N,N-diethylamino, N,N-dipropylamino, methylamino,ethylamino, propylamino, etc., acylamino having 2 to 3 carbon atoms suchas acetylamino, propionylamino, etc. or acyloxy having 2 to 3 carbonatoms such as acetyloxy, propionyloxy, etc. One or more of thesesubstituents, either the same or different, may occur in optionalpositions of the aryl group.

The alkyl group designated by R² may be any straightchain, branched,saturated or unsaturated alkyl group having 1 to 4 carbon atoms such asmethyl, ethyl, propyl, isopropyl, allyl, butyl, isobutyl, tert.-butyl,etc.

The compounds of general formula (I) and the derivatives at the carboxylfunction thereof have prominent analgetic, antipyretic,anti-inflammatory and other actions, and show low toxicity and less sideeffects. Taking advantage of these properties, these compounds cansafely be used as analgesics, antipyretics, anti-inflammatory agents andother drugs. When a compound (I) is used as such a medicine, it can beadministered, either as it is or in admixture with a pharmaceuticallyacceptable vehicle, excipient or/and diluent, orally or parenterally invarious dosage forms such as powders, granules, tablets, capsules,suppositories and injections. When any of the compounds is used for thepurpose of treating such diseases as chronic articular rheumatism,arthritis deformans, spondylosis deformans, arthralgia and lumbago, itis administered orally at the normal daily dose for human adults ofabout 10 to 1000 mg. or non-orally in amounts of 5 to 500 mg. per dosefor adult humans.

The compounds of formula (I) and the derivatives at the carboxylfunctions thereof can be prepared by the various process steps describedbelow. ##STR3##

Referring to the above formulas (I-a), (I-b), (III-a), (III-b), (III-c),(IV), (V), (VI), (VII), (VIII), (IX) and (X), R¹ has the meaning givenabove. R³ and R⁴ in formulas (IX), (IX'), (X) and (X') are each asubstituted mercapto group; R³ and R⁴ together may form a ring. Thesubstituted mercapto group may for example be straight-chain or branchedlower alkyl mercapto groups (e.g. methyl-, ethyl-, propyl-,butyl-mercapto, etc.), substituted lower alkylmercapto group (e.g.mercaptoalkyl-, aminoalkyl-mercapto, etc.) arylmercapto groups (e.g.phenylmercapto, etc.), substituted aryl mercapto groups (e.g.p-tolylmercapto, etc.), aralkylmercapto group (e.g. benzylmercapto,etc.) or the like. The substituted mercapto groups mentioned above maytake the form of S-oxide. R⁸ in formula (I-b) has the same meaning asalkyl group designated by R².

Referring to the formulas (VII) and (VII'), X is a hydroxyl groupconverted to a reactive ester. The hydroxyl group converted to areactive ester is exemplified by halogens such as chlorine, bromine oriodine and the residues of alkyl-, substituted alkyl-, aryl- andsubstituted-arylsulfonic acid esters such as methanesulfonic acid ester,trichloromethanesulfonic acid ester, o-toluenesulfonic acid ester,p-toluenesulfonic acid ester, o-nitrobenzenesulfonic acid ester,p-nitrobenzenesulfonic acid ester, o-chlorobenzenesulfonic acid ester,p-chlorobenzenesulfonic acid ester, β-naphthalenesulfonic acid ester,etc.

The reaction of Step A is carried out by subjecting a compound ofgeneral formula (IV) or a reactive derivative at the carboxyl functionthereof to intramolecular cyclization reaction.

The said reactive derivative of carboxylic acid (IV) may be any oneinsofar it is instrumental in the attainment of the objects of thisstep. Thus, for example, acid halides, acid anhydrides, esters, etc. maybe mentioned. As the acid halides, there may be mentioned, among others,the corresponding acid chloride, acid bromide, acid iodide and acidfluoride. As said acid anhydride, there may be mentioned, by way ofexample, the anhydride of carboxylic acid (IV) and the mixed anhydridesof carboxylic acid (IV) and another acid (e.g. organic acids such asformic acid, acetic acid, etc. and inorganic acids such as silicic acid,boric acid, etc.). The ester may for example be the p-nitrophenyl esterof compound (IV).

The intramolecular cyclization reaction according to this invention isgenerally conducted with advantage in the presence of a catalyst. Assaid catalyst, any of the catalysts which are commonly useful inFriedel-Crafts reactions, i.e. Friedel-Crafts catalysts, can beutilized.

For example, Lewis acid (e.g. aluminum chloride, aluminum bromide,aluminum fluoride, iron chloride, iron bromide, antimony chloride,antimony bromide, titanium chloride, tin chloride, tin bromide, zincchloride, zinc bromide, bismuth chloride, boron trifluoride, etc.);mineral acids such as sulfuric acid, phosphoric acid, polyphosphoricacid, etc.; and hydrogen fluoride to name but a few. When a Lewis acid,among said catalysts, is employed, an alkali metal halide (e.g.potassium chloride, sodium chloride, sodium bromide, potassium bromide,sodium iodide, potassium idodide), for instance, may be added to thereaction system. While the proportion of such a catalyst is more or lessoptional, it is preferably in the range of about 1 to 10 moles to eachmole of carboxylic acid (IV) or its reactive derivative. It should,however, be understood that when said mineral acid or hydrogen fluorideis employed as the catalyst, it may be used in large excess so that thecatalyst will function as the solvent as well. The reaction of this stepmay be carried out in the absence of a solvent or in the presencethereof. The solvent for this purpose may be any solvent only if it isinert to the contemplated reaction. Thus, nitrobenzene and halogenatedhydrocarbons (e.g. methylene chloride, ethylene chloride,1,1,2,2-tetrachloroethane, chlorobenzene, dichlorobenzene, etc.) may bementioned by way of example. While the reaction conditions including thereaction temperature and time are more or less optional, the preferredtemperature range is from room temperature to about 200° C.

The compound of general formula (V) thus obtained can be easily isolatedand purified by conventional separation-purification procedures such asextraction, distillation, recrystallization, chromatography, etc.

The reaction of Step B is carried out by reducing a compound of thegeneral formula (V).

This reduction can be achieved by any procedure for reducing a carbonylgroup to an alcohol. For practical purposes, there may be exemplifiedseveral kinds of the reduction procedures, namely, the reductionprocedure involving the use of a metal hydride such as sodiumborohydride or lithium aluminum hydride, the catalytic reductionprocedure which involves the use of a metal catalyst such as palladium,nickel, platinum, iron, rhodium, iridium or the like; the reductionprocedure involving the use of an alkali metal, e.g. sodium, lithium,potassium or the like together with a solvent which can act as hydrogendonor, e.g. alcohol, liquid ammonia or the like; and the reductionprocedure in which a metal complex compound of a metal such as rhodium,iridium or the like is employed. While each of these reductionprocedures generally proceed under cooling to heating and the reactiontemperature and time are not particularly critical, the preferredtemperature range is from about -35° to about 100° C.

In the case of catalytic reduction, hydrogen is introduced at normalpressure or at elevated pressure, there being no particular limitationupon the pressure of hydrogen. When lithium aluminum hydride isemployed, it is preferable to use anhydrous ether solvents (e.g. ethylether, propyl ether, isopropyl ether, tetrahydrofuran, dioxane, ethyleneglycol-dimethyl ether, ethylene glycol-diethyl ether, etc.), whileliquid ammonia and dry alcohols (e.g. methanol, ethanol, propanol,isopropanol, butanol, isobutanol, etc.), among others, are suited whenalkali metals are employed. In other cases, water, alcohols, ethers,etc. are used, although there is no particular limitation upon the typeof solvent unless such a solvent do not hinder the contemplatedreduction. The compound of general formula (VI) thus obtained can beisolated and purified by per se known procedures such as distillation,recrystallization, column chromatography, etc.

The reaction of Step C is carried out by subjecting a compound of theformula (VI) to a reaction leading to a reactive ester to obtain acompound of formula (VII).

As regards the reaction leading to a reactive ester, there may bementioned halogenation and reactions leading to sulfonic acid esters.

The halogenation reaction may be conducted by, for example, theprocedure wherein a hydrogen halide in anhydrous conditions or anaqueous solution (e.g. hydrogen chloride gas, hydrogen bromide gas,hydrochloric acid, hydrobromic acid, hydroiodic acid, etc.); a thionylhalide (e.g. thionyl chloride, thionyl bromide, thionyl iodide, etc.); aphosphorus halide (e.g. phosphorus pentachloride, phosphorustrichloride, phosphorus tribromide, phosphorus triiodide, etc.);phosphorus oxychloride; red phosphorus and a halogen such as bromine oriodine; an alkali metal iodide (e.g. sodium iodide, potassium iodide,etc.) and phosphoric acid, among others, is/are permitted to act, eitheralone or in combination, upon compound (VI). The reaction may beconducted in the presence or absence of a catalyst. The catalyst isgenerally selected from among organic amines, e.g. pyridine, aromaticamines (e.g. dimethylaniline, diethylaniline, etc.) and aliphatic amines(e.g. triethylamine etc.).

The reaction proceeds in the presence or absence of a solvent. Thesolvent, if employed, may be any type of solvent insofar as it is inertto the reaction. Examples of the solvent inert to the reaction includebenzene, toluene, xylene, chlorobenzene, hexane, halogenatedhydrocarbons (e.g. chloroform, methylene chloride, ethylene chloride,1,1,2,2-tetrachloroethane, etc.). While the reaction temperature dependsupon the reagents and solvent, if any, to be employed, the reactiongenerally proceeds over the temperature range of under cooling to underheating, preferably at about 0° to about 100° C, there being noparticular restriction on the reaction time.

When the alcohol of general formula (VI) is to be converted to asulfonic acid ester, the sulfonic esterification reaction is employed.For example, the sulfonic acid or sulfonyl chloride corresponding to oneof the sulfonic acid esters mentioned in the definition of X in compound(VII) is reacted with the alcohol of general formula (VI). While thereaction proceeds in the absence of a catalyst, it can be conducted moreadvantageously in the presence of a catalyst. As the catalyst, a basiccatalyst is ordinarily employed. More common species of the catalyst aredimethylformamide and pyridine as well as the aromatic amines andaliphatic amines mentioned in halogenation of this step. As regards thesolvent, such a basic agent may be used in a large excess so that itwill function as the solvent as well. It is also possible to employsolvents inert to the reaction such as benzene, toluene, xylene,chlorobenzene, hexane, halogenated hydrocarbons (e.g. chloroform,methylene chloride, ethylene chloride, 1,1,2,2-tetrachloroethane, etc.).While the reaction temperature and time are virtually optional, thepreferred temperature range is from about 0° to about 50° C.

The compound (VII) thus obtained can be separated and purified by a perse known separation purification procedures such as recrystallization,distillation, chromatography, etc.

The reaction of Step D is carried out by reacting a compound of thegeneral formula (VII) with a cyanide.

As the cyanide to be reacted with compound (VII), there may be mentionedthe salts of metals of Group I of the Periodic Table of the Elements.Thus, for example, the sodium salt, potassium salt, copper salt, silversalt, etc. can be employed.

The reaction may be generally carried out in the absence or presence ofa catalyst. As said catalyst, there may be mentioned quaternary ammoniumhalides. The quaternary ammonium ions may be substituted by alkyl groupsof about 1 to 20 carbon atoms. Among them are those comprising astraight-chain or branched alkyl group including, for exampletetraalkylammonium, alkylaralkylammonium, tetraaralkylammonium, etc. Forexample, tetrabutylammonium, triethylhexadecylammonium,triethylbenzylammonium, etc. may be mentioned. More common species ofhalide ion are chloride, bromide, etc. Further, instead of using acyanide and the catalyst, use may be made of an ammonium cyanide. Inthis connection, the ammonium ion may be any of the above-mentionedammonium ions.

While the reaction time, temperature and other conditions are notparticularly critical, the reaction temperature is preferably in therange of about 0° to about 100° C. As the solvent to be employed whenthe reaction is to be carried out without a catalyst, it is advantageousto employ, for example, the following: dimethylsulfoxide,N,N-dimethylformamide, hexamethylphosphoric triamide, alcohols (e.g.methanol, ethanol, propanol, isopropanol, etc.), acetone and water. Whenuse is made of an ammonium cyanide or a catalyst, it is advantageous touse water as the solvent.

The resultant compound of general formula (VIII) can be separated andpurified by per se known procedures such as distillation,recrystallization, chromatography, etc.

The reaction of Step E is carried out by subjecting a compound of thegeneral formula (VIII) to solvolysis.

The solvolysis may generally be hydrolysis with water as the solvent oralcoholysis with an alcohol as the solvent.

Aside from them, there are cases in which a phenol, for instance, isused as the solvent. The solvolysis is generally conducted in thepresence of a catalyst, examples of which include hydrogen halides (e.g.hydrogen chloride, hydrogen bromide, hydrogen iodide), mineral acidssuch as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuricacid, phosphoric acid, polyphosphoric acid, etc.; organic acids such asformic acid, acetic acid, p-toluenesulfonic acid, β-naphthalenesulfonicacid, etc.; Lewis acids mentioned in the explanation of Step A; alkalimetal hydroxide such as sodium hydroxide, potassium hydroxide, etc.;alkaline earth metal hydroxide such as calcium hydroxide, bariumhydroxide, etc.; metal alcoholates made up of lower alcohols comprisingalkyls of about 1 to 4 carbon atoms (e.g. methanol, ethanol, propanol,isopropanol, butanol, isobutanol, sec.-butanol, tert-butanol, etc.) withalkali metals such as sodium, potassium, etc.; hydrogen peroxide,per-acids such as peracetic acid, perbenzoic acid, etc. These catalystsare at times used alone and at other times used in combination. Whilethe reaction temperature varies with the type of catalyst used, thereaction may generally be carried out under cooling, at room temperatureor under heating, preferably at about 0° to about 100° C. The reactiontime is virtually optional. The structure of product (I-a) depends uponthe reaction conditions used and the reaction conditions may be selectedaccording to the contemplated compound.

For example, when use is made of an alcohol as the solvent for compoundof general formula (VIII) and of a hydrogen halide, e.g. hydrogenchloride, hydrogen bromide, etc., sulfuric acid, p-toluenesulfonic acidor the like as the catalyst, there is obtained a compound (I-a) whosecarboxyl group is converted to the ester corresponding to alcohol used.When a compound (VIII) is hydrolyzed with water, there is obtained acompound (I-a) whose carboxyl group is converted to an carbamoyl group(--CONH₂), and under severe conditions, the acid amide is furtherhydrolyzed to give a compound (I-a) whose carboxyl group is in the formof free acid. In this procedure, one may of course isolate the acidamide formed and, then, hydrolyze it into carboxylic acid.

The acid amide is obtained when concentrated sulfuric acid, aconcentrated solution of hydrogen halide or the like is employed as thecatalyst under cooling, when polyphosphoric acid is used as the catalystunder heating; or when boron trifluoride is employed at roomtemperature, to name but a few instances. There is obtained a compound(I-a) whose carboxyl group is free when use is made of sulfuric acid, analkali metal hydroxide or the like under heating. When compound (VIII)is solvolyzed with a solvent other than water, there are cases,according to the conditions used, in which the free acid is directlyproduced, bypassing the formation of acid amide.

The compound of general formula (I-a) which has been produced by thereaction of this step can be purified by per se known separatoryprocedures such as recrystallization, distillation, chromatography, etc.

When the resultant product compound is a free carboxylic acid of generalformula (I-a), the resultant product compound can be converted toderivatives at its carboxyl function by procedures which are known perse (e.g. the production of salts by neutralization or other procedure;esterification by means of an alcohol in the presence of acid, amidationwhich comprises reacting the compound with an amine; and amidation whichcomprises the steps of converting the compound to an acid halide and,then, reacting the latter with an amine). Conversely, such a derivativeat the carboxyl function can be converted to the free carboxylic acid byprocedures which are known per se (e.g. hydrolysis in the presence ofbase or acid). Said derivatives at the carboxyl function can be furtherconverted to other types of derivatives by procedures which are knownper se (e.g. amidation which comprises reacting the ester with an amine;esterification which comprises reacting the amide with an alkylpolyphosphate; etc.).

The cyclic carboxylic acid of general formula (I-a) which is obtainableby the method hereinbefore described has an asymmetric carbon atom in1-position of its molecule and, therefore, can be resolved through amethod known per se into optical isomers, i.e. d- and l-compounds.

Thus, optically active forms of the free carboxylic acid derivatives canbe isolated by the steps of dissolving the racemic free acid in asuitable inert solvent such as chloroform, acetone, benzene, hexane,ether, water, methanol, ethanol, acetonitrile or the like, reacting thesame with an optically active base, separating the resultant salt oramide into diastereoisomers by taking advantage of their dissimilarityin solubility and, then, treating them with an acid. The opticallyactive free carboxylic acid can also be isolated by the steps ofpreparing an ester from the racemic free acid and a suitable opticallyactive alcohol, resolving the ester into diastereoisomers by a procedurewhich is known per se such as recrystallization, distillation orchromatography and, then, hydrolyzing the ester with an acid or a base.The optically active base to be thus used is exemplified by basic aminesuch as quinine, brucine, cinchonidine, cinchonine, dehydroabietylamine,hydroxyhydrindamine, methylamine, morphine, α-phenylethylamine,phenyloxynaphtylmethylamine, quinidine, strychnine, etc., basic aminoacid such as lysine, arginine, etc., ester of amino acid, etc.

The optically active alcohol is exemplified by borneol, menthol,2-octanol, etc.

The cyclic carboxylic acid derivative of general formula (I-a) which hasbeen obtained by an optical resolution procedure such as those describedabove can be converted to an optically active derivative at its carboxylfunction by the above-mentioned procedures which are known per se.

The steps B', C', D' and E' are carried out by taking the similarprocedures to those of Steps B, C, D and E, respectively. In thesecases, the compounds (V'), (VI'), (VII') and (VIII') used as startingcompounds in each of Steps B', C', D' and E' may be derivatives at thecarboxyl function thereof. As the derivatives at the carboxyl function,there are mentioned those defined in the definition of the derivativesat the carboxyl function of compound (I).

The Step E" is carried out by taking the similar procedures to those ofStep E.

The reaction of Step F is carried out by reacting a compound (V) with acompound of general formula:

    R.sup.3 -- CH.sub.2 -- R.sup.4                             (XI)

wherein R³ and R⁴ have the meanings given above.

As compounds of formula (XI), there are mentioned 1,3-dithian,1,3,5-trithian, methyl methylthiomethylsulfoxide, methylmethylthiomethylsulfide, ethyl ethylthiomethylsulfoxide, ethylethylthiomethylsulfide and the like.

This reaction is conveniently conducted in the presence of a base. Assaid base, there may be mentioned, by way of example, alkali metalhydroxide (sodium hydroxide, potassium hydroxide, etc.), alkali metalhydride (e.g. sodium hydride, lithium hydride, etc.), alkali metalalcoholate (e.g. sodium methylate, sodium ethylate, sodiumtert-butylate, potassium tert.-butylate, sodium tert.-amylate, etc.),alkali metal amide (e.g. sodium amide, potassium amide, lithium amide,sodium piperidide, potassium piperidide, lithium piperidide, sodiumdiethyl amide, potassium diethylamide, lithium diethylamide, sodiumdiisopropylamide, potassium diisopropylamide, lithium diisopropylamide,lithium bis-trimethylsilylamide, lithium dicyclohexylamide, etc.),n-butyl lithium, triton-B, etc.

This reaction is generally conducted in the presence of a solvent.Virtually any solvent can be used for this purpose, only if it is inertto the reaction. For example, ethers (e.g. diethyl ether,tetrahydrofuran, dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane,diethylene glycol dimethyl ether, etc.), benzene toluene, xylene,methanol, ethanol and water can be employed with advantage.

While the amount of compound (XI) and that of the base are largelyoptional, it is desirable to each of them in the proportion of about 1to about 2 moles per mole of compound (V).

The reaction temperature may preferably range from about -30° C to theboiling point of the solvent used and the reaction time is preferablyabout 5 to 25 hours.

The compound (IX) thus obtained can easily be isolated by a conventionalmethod known per se.

The reaction of Step G is carried out by subjecting a compound (IX) todehydration.

In the dehydration, use may be made of dehydrating agent with advantage.As the dehydrating agent for this reaction, there may be used, withadvantage, mineral acids (e.g. sulfuric acid, phosphoric acid,phosphorous acid, hydrochloric acid, etc.), phosphorus oxychloride,thionyl chloride, arylsulfonic acids (e.g. benzenesulfonic acid,p-toluenesulfonic acid, β-naphthalenesulfonic acid, etc.), acetic acidand its derivatives (e.g. trifluoroacetic acid, trichloroacetic acid,etc.) and lower alkylsulfonic acid (e.g. methanesulfonic acid,ethanesulfonic acid, propanesulfonic acid, etc.), to name but a few. Thesolvent to be used for the purpose may be virtually any type of solventinsofar as it does not interfere with the reaction. The reactiontemperature may be a reduced temperature, i.e. under cooling, to about150° C, the reaction temperature being more or less optional.

The compound of formula (X) thus obtained may assume the two structuresshown below as (X-a) and (X-b). ##STR4##

The reaction of Step H is carried out by subjecting a compound (X) tosolvolysis.

The solvolysis generally refers to hydrolysis with water as the solvent,or alcoholysis which employs as the solvent an alcohol (e.g. methanol,ethanol, propanol, isopropanol, butanol, isobutanol, sec.-butanol,tert.-butanol, benzyl alcohol, etc.), although phenol, for one, may alsobe used as the solvent.

The solvolysis is generally conducted in the presence of a catalyst. Assaid catalyst, there may be employed hydrogen halide (e.g. hydrogenchloride, hydrogen bromide, hydrogen iodide, etc.); mineral acids suchas hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid,phosphoric acid, polyphosphoric acid, etc.; organic acids such as formicacid, acetic acid, p-toluenesulfonic acid, β-naphthalenesulfonic acid,etc.; heavy metal salts (e.g. mercury chloride, mercury bromide, mercuryfluoride, mercury sulfate, copper chloride, copper bromide, etc.); toname but a few. These catalyst are at times used alone or used at othertimes in a combination of two or more. While the reaction temperaturedepends upon such reaction conditions as the types of solvent andcatalyst, the reaction may generally be carried out under cooling, atroom temperature or under heating, preferably at about 0° to about 120°C.

The reaction time is optional for all practical purposes. The desiredcompound (I-a) of this reaction is obtained in various forms at thecarboxyl function thereof under the influence of reaction conditions.The desired compound (I-a) having the desired species of derivative atthe carboxyl function can be obtained by selecting the proper reactionconditions. For example, when compound (X) is hydrolyzed, the resultantproduct (I-a) is in the form of free acid. Alcoholysis of compound (X)gives a compound (I-a) whose carboxyl group is an esterified carboxylgroup corresponding to the alcohol used. Further by selecting reactionconditions of said solvolysis, there can also be obtained contemplatedcompound (I-a) such that the carboxyl group in compound (I-a) has beenesterified or de-esterified.

The compounds (I-a) can be resolved into optical isomers by per se knownprocedures which may be referred to those mentioned in Step E.

The Steps F', G' and H' are carried out by taking the similar proceduresto those of Steps F, G and H, respectively. In these cases, thecompounds (V'), (IX') and (X') used as starting compounds in each ofSteps F', G' and H' may be derivatives at the carboxyl function thereof.As the derivatives at the carboxyl function, there are mentioned thosedefined in the definition of the derivatives at the carboxyl function ofcompound (I).

The reaction of Step I is carried out by reacting a compound of formula(V') with a compound of general formula

    R.sup.1 -- H                                               (XII)

wherein R¹ has the meaning given above.

The starting compound (V') may be a reactive derivative at the carboxylfunction thereof. As the reactive derivative at the carboxyl function,there are mentioned a derivative at the carboxyl function defined in thestarting compounds in Step B' as well as p-nitrophenyl ester and acidhalide such as acid chloride, acid bromide, acid iodide, etc. Whencompound (V') is a free carboxylic acid, it may first be converted to areactive derivative at the carboxyl function and, then, the derivativebe subjected to the contemplated reaction. When compound (V') is areactive derivative, it may first be converted to the free carboxylicacid which, in turn, is subjected to the contemplated reaction. Thisreaction is generally conducted with advantage in the presence of acatalyst which may be any of the agents that can ordinarily be used ascatalysts in Friedel-Crafts reactions, that is to say any of theso-called Friedel-Crafts catalysts. Thus, metal halides (e.g. aluminumchloride, aluminum bromide, aluminum fluoride, iron chloride, ironbromide, antimony chloride, antimony bromide, titanium chloride, tinchloride, tin bromide, zinc chloride, zinc bromide, bismuth chloride,etc.); Lewis acids such as boron fluoride; mineral acids such assulfuric acid, phosphoric acid, polyphosphoric acid, etc.; hydrogenfluoride; etc. may be mentioned by way of example. The reaction isadvantageously conducted in the presence of a solvent which may be anaromatic compound of general formula (XII) or any of the solvents inertto the reaction. Said solvents inert to the reaction include, amongothers, carbon disulfide, nitrobenzene, halogenated hydrocarbons (e.g.methylene chloride, ethylene chloride, 1,1,2,2-tetrachloroethane, etc.),etc.

When sulfuric acid, polyphosphoric acid or hydrogen fluoride, forinstance, is used as the catalyst, it can be used in a large excess sothat it will function as the solvent as well. When a Friedel-Craftscatalyst is employed, its proportion is ordinarily about 1 to 6 molesper mole of the carboxylic acid of general formula (V') or its reactivederivative. While the reaction conditions such as temperature and timeare not particularly critical, the practically desirable reactiontemperature is somewhere between -15° C and the neighborhood of theboiling point of the solvent used. The temperature may be increased ordecreased within the above range. The reaction time ordinarily rangesfrom about 1 to 5 hours, although it depends upon the species ofstarting compound, catalyst and solvent. The resultant compound ofgeneral formula (V) can be separated and purified by procedures whichare known per se, such as distillation, recrystallization, columnchromatography, etc.

The Steps I' and I" is carried out by taking a similar procedure to thatof Step I.

In these Steps, the starting compounds may be reactive derivatives atthe carboxyl function on benzene ring of compound (VIII') or (I'). Asthe reactive derivatives, there are mentioned those defined in thestarting compound in Step I. Further, the starting compound (I') of StepI" may be a derivative at the carboxyl function other than that onbenzene ring. As the derivative, there are mentioned those defined incompound (I).

Though, in the reaction of Step I", there is produced a mixture ofcompound (I-a) and compounds of following formula: ##STR5## wherein R¹has the meanings given above, the contemplated compound (I-a) can beseparated and purified by per se known separatory procedures such asrecrystallization, distillation, chromatography, etc.

The compounds (I-a) can be obtaind in a suitable form such as free acid,ester, salt and the like by taking the procedures mentioned in Step E.

Further, the compounds (I-a) can be resolved into optical isomers by asimilar manner to that described in Step E.

The reaction of Step J is carried out by reacting a compound of generalformula (II) with a compound of general formula;

    R.sup.1 -- COOH                                            (XIII)

wherein R¹ has the meaning given above.

The compound (II) may be a derivative at the carboxyl function thereof.As the derivative at the carboxyl function, there are mentioned thosedefined in compound (I). The compound (XIII) may be a reactivederivative at the carboxyl function thereof. As the reactive derivativeat the carboxyl function, there are mentioned those defined in thestarting compound (IV) of Step A. The proportion of said carboxylic acidof general formula (XIII) or said reactive derivative of (XIII) ispreferably about 1 to about 10 moles to each mole of said carboxylicacid of general formula (II) or derivative at the carboxyl function of(II) for practical purposes.

Generally speaking, the reaction is advantageously conducted in thepresence of a solvent and a catalyst. The solvent may be any solventthat is inert to the reaction; for example, carbon disulfide,nitrobenzene, halogenated hydrocarbons (for example, methylene chloride,ethylene chloride, 1,1,2,2,-tetrachlorethane, chlorobenzene,dichlorobenzene etc.) and so forth. As the catalyst for this reaction,use may be made of the substances which can be ordinarily used ascatalysts in Friedel-Crafts reactions, i.e. the so-called Friedel-Craftscatalysts. While the proportion of such catalyst usually need not beover about 1 to 1.5 moles per mole of said carboxylic acid of generalformula (XIII) or said reactive derivative thereof, any of theabove-mentioned mineral acids, hydrogen halide, etc. may be used inlarge excess so that it will function as the solvent as well. Thereaction conditions such as temperature and time are largely optional.

However, for practical purposes, the reaction temperature ordinarilyranges from -15° C to the boiling point of the solvent employed and thereaction system may be cooled or heated to a suitable extent within saidtemperature range. Ordinarily the reaction time is about 1 to about 4hours, although it depends upon the species of starting compounds,catalyst and solvent used.

The reaction of this invention gives rise not only to the contemplatedcompound (I-a) or a derivative at the carboxyl function of (I-a) but attimes to a compound of general formula: ##STR6## wherein R¹ and n havethe meanings given above.

The compounds (I-a) can be separated and purified by a per se knownseparatory procedures such as recrystallization, distillation andchromatography.

The compound (I-a) can be obtained in a suitable form such as free acid,ester, salt, etc. by taking the procedures mentioned in Step E.

Further, the compound (I-a) can be resolved into optical isomers by asimilar manner to that described in Step E.

The reaction of Step K is carried out by oxidizing a compound (III-a).

As the procedures of oxidation, use may be made of any procedures bywhich a methylene group can be oxidized to a carbonyl group. Thus,oxidation procedures utilizing for example, chromic acid, permanganicacid, manganese dioxide, selenium dioxide, cerium, N-bromosuccinimide,etc. as the oxidizing agents may be used to advantage. Moreparticularly, in the chromic acid oxidation process, use may be made,with advantage, of any of such oxidizing agents as chromic anhydride,chromic acid, dichromates (e.g. ammonium dichromate, potassiumdichromate, sodium dichromate, etc.), chromates (e.g. ammonium chromate,potassium chromate, silver chromate, cobalt chromate, cesium chromate,sodium chromate, barium chromate, etc.), chromic acid chloride (e.g.chromyl chloride), etc. The solvent for use in this process may forexample be an acid, e.g. sulfuric acid, acetic acid or the like; water;and an organic solvent, e.g. acetone, benzene, ether, acetic anhydrideor the like. These solvents are used either alone or as a mixture. Inthe premanganic acid oxidation, use is desirably made of such oxidizingagents as permanganates (e.g. potassium permanganate, sodiumpermanganate, barium permanganate, calcium permanganate, magnesiumpermanganate, zinc permanganate, etc.). As the reaction solvent, abasic, neutral or acid aqueous solution is desirable and, in certaincases, an organic solvent such as acetone, benzene or toluene may beconcomitantly present. In the manganese dioxide oxidation, manganesedioxide and sulfuric acid are desirably used as the oxidizing agent andsolvent, respectively. The selenium dioxide oxidation is desirablycarried out with selenium dioxide as the oxidizing agent in water,acetic anhydride, acetic acid, dioxane or the like as the solvent. Inthe case of cerium oxidation, cerium ammonium nitrate [Ce(NH₄)₂ (NO₃)₆ ]is used as the oxidizing agent, the solvent being either asingle-component solvent or a solvent mixture, for example, water,mineral acids (e.g. perchloric acid, nitric acid, sulfuric acid, etc.),organic acids (e.g. formic acid, acetic acid, propionic acid, etc.),acetonitrile, tetrahydrofuran, acetone, dioxane, etc. may be employedfor this purpose.

In these oxidizing reactions, the reaction temperature is somewherewithin the range of under cooling with ice to about 100° C, the reactiontime being more or less optional.

The contemplated compound thus obtained can be separated and purified byprocedures which are known per se, such as distillation,recrystallization, column chromatography, etc.

The Steps K' and K" are carried out by taking the procedures similar tothose of Step K:

In the reaction of Step K", the starting compound may be a derivative atthe carboxyl function of compound (III-c). As the derivative, there arementioned those defined in compound. (I).

The objective compounds of these reactions can be separated and purifiedby the per se knwon separatory procedures such as recrystallization,distillation and chromatography.

The compound (I-a) can be recovered in a suitable form such as freeacid, ester, salt, etc. by taking the procedures mentioned in Step E.

Further, the compound (I-a) can be resolved into optical isomers by sucha per se known manner as described in Step E.

The reaction of Step L is carried out by reacting a compound of generalformula (V) with sulfonylmethylisonitrile compound.

Said sulfonylmethylisonitrile compound may for example be a compoundrepresened by general formula

    R.sup.9 SO.sub.2 CH.sub.2 NC                               (XV)

wherein R⁹ means an aryl, aralkyl or alkyl group. The aryl group standsfor, for example, phenyl or naphthyl whose aromatic nucleus may besubstituted by alkyls (e.g. methyl, ethyl, etc.), halogens (e.g.chlorine, bromine, etc.), alkoxyls (e.g. methoxy, etc.), etc. inoptional positions. Particularly advantageous for practical purposes arephenyl, p-tolyl, etc. The aralkyl group represented by R⁹ may forexample be benzyl or phenethyl; the alkyl group which is alsorepresented by R⁹ may for example be methyl, ethyl n-propyl, isopropyln-butyl, isobutyl, sec.-butyl, tert.-butyl or the like.

This reaction consists in reacting 1 to 1.5 moles of (XV) with each moleof (V) in the presence of substantially 1 to 3 moles per mole of (V) ofa base in a solvent. Preferred species of the solvent are mixtures ofethers such as dimethoxyethane, diethoxyethane, tetrahydrofuran, etc.,with lower alcohols such as methanol, ethanol, tert.-butanol, etc., andthe mixing ratio is preferably 2 to 20 parts of such an ether to eachpart of an alcohol and, for better results, within the range of 5 to 10parts to 1 part. The base is exemplifed by metal alcoholates which areobrtainable from lower alcohols, e.g. methanol, ethanol, t-butanol,etc., and alkali metals, e.g. sodium, potassium, etc. In the presence ofsuch a base, the reaction proceeds with increased advantage.

The reaction temperature is selected from within the range of 0° to 100°C according to the reactivity of the starting compounds and the types ofsolvent, base, etc. to be used. Particularly preferred is a temperaturewhich lies somewhere between 10° and 40° C.

Generally, the reaction goes to conclusion in 1 to 6 hours.

The desired product (VIII) can be isolated by per se known procedures.

The Steps L' and L" are carried out by taking the procedures similar tothose of Step L.

The starting compound of Step L' may be a derivative at the carboxylfunction of compound (V'). As the derivative at the carboxyl function,there are mentioned those defined in the starting compound (V') of StepB'.

The reaction of Step M is carried out by subjecting a compound ofgeneral formula (I-a) to alkylation.

The alkylation is conducted by reacting with the compound (I-a) with acompound of general formula

    R.sup.8 -- X                                               (XVI)

wherein R⁸ is an alkyl having 1 to 4 carbon atoms and X has the meaninggiven above.

As the alkyl shown by R⁸, there are mentioned methyl, ethyl, propyl,i-propyl, allyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, etc.

This reaction proceeds with advantage in the presence of a base. As thebase, there are mentioned alkali metal hydroxide (e.g. sodium hydroxideand potassium hydroxide), alkali metal hydride (e.g. sodium hydride andlithium hydride), alkali metal alcoholate (e.g. sodium methylate, sodiumethylate, sodium tert.-butylate, potassium tert.-butylate and sodiumtert.-amylate), alkali metal amide (e.g. sodium amide, potassium amide,lithium amide, sodium piperidide, potassium piperidide, lithiumpiperidide, sodium diethylamide, potassium diethylamide, sodiumdiisopropylamide and lithium diisopropylamide), etc. As the solvent tobe used, there are mentioned alcohols (e.g. methanol, ethanol, propanol,butanol and tert.-butanol), ethers(e.g. diethylether, tetrahydrofuran,dioxane, methoxyethane, 1, 2-diethoxyethane, 1,2-dimethoxyethane,dimethylether), benzene, toluene, xylene, dimethylsulfoxide,N,N-dimethylformamide, hexamethylphosphoric triamide, liquid ammonia,diethylamine, diisopropylamine, etc.

The base is usually used in an amount of 1 to 10 moles per mole ofcompound (I-a) and compound (XVI) is usually used in an amount of 1 to 3moles per mole of a base. While the reaction conditions such astemperature and time are largely optional, the preferred temperaturerange is about 0° to about 50° C.

The compound (I-b) thus obtained can be separated and purified by per seknown separation-purification procedures such as recrystallization,distillation, chromatography, etc.

The compounds (I-b) can be recovered in a optional form such as freeacid, ester, salt and the like by taking similar procedures to thosementioned in Step E.

Further, the compounds (I-b) can be resolved into optical isomers by asimilar manner to that described in Step E.

Throughout the present specification the abbreviations "mg.", "g.","ml." and "° C", respectively refer to "milligram(s)", "gram(s)","milliliter(s)" and "degree(s) centigrade".

Although the following examples are further illustrative of thisinvention, these do not have any meaning of limiting or restricting thescope of this invention at all.

REFERENCE EXAMPLE 1

To 100 ml. of methylene chloride is added 50 g. of dry aluminumchloride. The mixture is stirred and 28 g. of benzoyl chloride is addeddropwise. While the solution is stirred at 30°-40° C, 16.4 g. of methylβ-phenylpropionate is added dropwise over a period of about 1 hour.After the drop-by-drop addition has been completed, the solution isstirred at 30°-40° C for 2 hours. After cooling, the solution is pouredinto ice-hydrochloric acid and extracted with methylene chloride. Theextract is washed with dilute hydrochloric acid, water, dilute aqueoussodium hydroxide and water in the order mentioned, followed by drying.The solvent is distilled off under reduced pressure and the residue ispurified by column chromatography (1 kg. of silica gel; eluted withbenzene). The described procedure gives methylp-benzoyl-β-phenylpropionate and methyl o-benzoyl-β-phenylpropionate.

To a solvent mixture of 20 ml. of ethanol and 100 ml. of water are added20 g. of the methyl o-benzoyl-β-phenylpropionate thus obtained and 15 g.of potassium hydroxide. The mixture is refluxed for 2 hours. Aftercooling, the solvent is distilled off and the residue is diluted withwater and washed with ether. The aqueous layer is acidified withhydrochloric acid and extracted with ether. The extract is washed withwater and dried. Then, the solvent is distilled off and the residue iscrystallized from benzene-hexane. The procedure giveso-benzoyl-β-phenylpropionic acid.

REFERENCE EXAMPLES 2-6

By the similar manner to Reference 1, following compounds are produced

    ______________________________________                                        Reference                                                                     example  Produced-compound                                                                              Starting compound                                   ______________________________________                                                o-(p-toluoyl)-β-phenyl-                                                                    p-toluoyl chloride                                  2       propionic acid    +                                                                             methyl β-phenyl-                                                          propionate                                                 o-(p-chlorobenzoyl)-β-                                                                     p-chlorobenzoyl                                             phenylpropionic acid                                                                            chloride                                            3                         +                                                                             methyl β-phenyl-                                                          propionate                                                 o-benzoyl-γ-phenyl-                                                                       ethyl γ-phenyl-                                       butylic acid      butylic acid                                        4                         +                                                                             benzoyl chloride                                            o-(p-toluoyl)-γ-                                                                          ethyl γ-phenyl-                                       phenylbutylic acid                                                                              butylic acid                                        5                         +                                                                             p-toluoyl chloride                                          o-(p-chlorobenzoyl)-                                                                            ethyl γ-phenyl-                                       γ-phenylbutylic acid                                                                      butylic acid                                        6                         +                                                                             p-chlorobenzoyl                                                                chloride                                           ______________________________________                                    

REFERENCE EXAMPLE 7

To 700 ml. of ice-cooled dry ether is added 15 g. of lithium aluminumhydride, followed by the addition of 61.8 g. of crystallineo-(p-chlorobenzyl)benzoic acid. The mixture is refluxed with stirringfor 5 hours, after which it is allowed to stand at room temperatureovernight and, then, the excess reagent is decomposed with ice-water.The organic layer is separated, washed with water and dried. The solventis distilled off under reduced pressure and the residue is distilledunder reduced pressure. The procedure gives o-(p-chlorobenzyl)benzylalcohol as a fraction boiling at 145°-155° C/0.1 mm mercury.

In 400 ml. of chloroform is dissolved 46.5 g. ofo-(p-chlorobenzyl)benzyl alcohol and, under stirring and cooling withice, 19 g. of phosphorus tribromide is added dropwise. After thedrop-by-drop addition has been completed, the mixture is stirred undercooling with ice for 1 hour and, then, at room temperature for 1 hour.The solution is allowed to stand overnight and washed three times withice cooled water, followed by drying over calcium chloride. The solventis distilled off under reduced pressure, whereupono-(p-chlorobenzyl)benzyl bromide is obtained as an oily residue. Thisproduct is used in the next reaction without purification.

In 100 ml. of ethanol is dissolved 4.8 g. of sodium metal and while thesolution is stirred at room temperature, 64 g. of diethyl malonate isadded dropwise. After the drop-by-drop addition has been completed, themixture is heated at 80°-90° C for 15 minutes and, then, cooled. Understirring, a mixture of 59 g. of o-(p-chlorobenzyl)benzyl bromide and 150ml. of dry benzene is added dropwise. After the dropwise addition hasbeen completed, the mixture is refluxed with stirring for 2 hours. Thesolvent is distilled off under reduced pressure and the residue isdiluted with water and extracted with benzene. The extract is washedwith water and dried. The solvent is then distilled off under reducedpressure and the residue is further distilled under reduced pressure.

The described procedure gives diethyl o-(p-chlorobenzyl)benzylmalonateas a fraction boiling at 175°-185° C/0.2 mm mercury.

In 70 ml. of water is dissolved 25 g. of potassium hydroxide, followedby the addition of 62.5 g. of diethyl o-(p-chlorobenzyl)benzylmalonate.The mixture is refluxed under stirring for 6 hours and, then, allowed tostand at room temperature overnight. To the reaction mixture is added300 ml. of water and, after the mixture is rendered acidic by theaddition of hydrochloric acid, it is cooled with ice.

The precipitate is collected and dissolved in a solvent mixture of ethylacetate and ether. The solution is washed with aqueous sodium chlorideand dried. The solvent is distilled off under reduced pressure,whereupon o-(p-chlorobenzyl)benzylmalonic acid is obtained.

Without purification, this product is decarboxylated by heating at160°-170° C for 3 hours, after which it is cooled. Recrystallizationfrom cyclohexane gives 3-[o-(p-chlorobenzyl)phenyl]propionic acid ascrystals melting at 107°-109° C.

To stirred polyphosphoric acid, prepared from 100 g. of phosphoruspentoxide and 70 ml. of phosphoric acid, 5.0 g. of3-[o-(p-chlorobenzyl)phenyl]propionic acid is added. The mixture isstirred at 110°-120° C for 2 hours. Upon addition of ice-water, yellowcrystals separate out. These crystals are collected by filtration,washed with water and dried. The crystals are purified by columnchromatography (silica gel; eluted with a 40 : 1 mixture of benzene andethyl acetate. The described procedure gives4-(p-chlorobenzyl)indan-1-one as crystals melting at 87°-88° C.

REFERENCE EXAMPLES 8-10

By a similar manner to Reference example 7, the following compounds areproduced.

    ______________________________________                                        Reference                                                                     example  Produced-compound                                                                              Starting compound                                   ______________________________________                                                4-benzylindan-1-one                                                                             o-benzylbenzoic                                     8       melting point:    acid                                                        71-73° C                                                               (n-hexane)                                                                    4-(p-methylbenzyl)-                                                                             o-(p-methylbenzyl)-                                         indan-1-one       benzoic acid                                        9       melting point:                                                                102-105° C                                                             (cyclohexane)                                                                 4-(p-methoxybenzyl)-                                                                            o-(p-methoxybenzyl)-                                        indan-1-one       benzoic acid                                        10      melting point:                                                                82-84° C                                                               (cyclohexane)                                                         ______________________________________                                    

EXAMPLE 1-(1)

Five g. of o-benzoyl-β-phenylpropionic acid, 13 g. of anhydrous aluminumchloride and 1.3 g. of sodium chloride are admixed together and heatedat 160° C for 1 hour. After cooling, water is added to the mixture,followed by extraction with chloroform. The extract is washed with a 5%aqueous solution of sodium bicarbonate and water in that order and,then, dried. The solvent is distilled off under reduced pressure and theresidue is dissolved in ethanol. The solution is decolorized withactivated carbon and recrystallized from ethanol. The procedure yields4-benzoylindan-1-one as crystals melting at 86°-88° C.

By a similar manner to Example 1-(1), the following compounds areproduced.

    ______________________________________                                        Example produced-compound                                                                             starting compound                                     ______________________________________                                               4-(p-toluoyl)indan-1-                                                                         O-(p-toluoyl)-β-phenyl-                                  one             propionic acid                                         1-(2)  m.p. 106-180° C                                                                        aluminum chloride                                             [cyclohexane]   sodium chloride                                               5-benzoyl-1-tetralone                                                                         O-benzoyl-r-phenylbutylic                              1-(3)  m.p. 72.5-73.5° C                                                                      acid                                                          [cyclohexane]   aluminum chloride                                                             sodium chloride                                               5-(p-toluoyl)-1-                                                                              O-(p-toluoyl)-r-                                              tetralone       phenylbutylic acid                                     1-(4)  m.p. 86-87° C                                                                          aluminum chloride                                             [cyclohexane]   sodium chloride                                        ______________________________________                                    

EXAMPLE 1-(5)

To 5.8 g. of o-(p-chlorobenzoyl)-β-phenylpropionic acid is added 50 ml.of thionyl chloride and the mixture is allowed to stand at roomtemperature overnight.

The excess thionyl chloride is distilled off under reduced pressure, and13 g. of anhydrous aluminum chloride and 1.3 g. of sodium chloride areadded to the resultant crude o-(p-chlorobenzoyl)-β-phenylpropionylchloride. The mixture is heated at 160° C for 1 hour. After cooling,water is added, followed by extraction with chloroform. The extract iswashed with a 5% aqueous solution of sodium bicarbonate and water in theorder mentioned and, then, dried.

The solvent is distilled off under reduced pressure and the residue iscrystallized from a 1:1 mixture of benzene and cyclohexane. Thedescribed procedure gives 4-(p-chlorobenzoyl)indan-1-one as crystalsmelting at 145.5°-146° C.

EXAMPLE 1-(6)

By a similar manner to Example 1-(5), 6 g. ofo-(p-chlorobenzoyl)-γ-phenyloutyric acid is converted too-(p-chlorobenzoyl)-γ-phenylbutyryl chloride which, in turn, is reactedwith 13 g. of anhydrous aluminum chloride and 1.3 g. of sodium chlorideto prepare 5-(p-chlorobenzoyl)-1-tetralone. melting point: 96°-98° C(recrystallization solvent: cyclohexane).

EXAMPLE 2-(1)

To 120 ml. of ethanol is added 5.7 g. of methyl 1-oxoindan-4-carboxylateand the mixture is stirred at room temperature.

Then, 600 mg. of sodium borohydride is added and, after stirring for 90minutes, 4 ml. of acetone is added. The mixture is further stirred for30 minutes, after which the solvent is distilled off under reducedpressure.

To the residue are added water and dilute hydrochloric acid, followed byextraction with ether. The extract is washed with water and a saturatedaqueous solution of sodium chloride and, then, dried. Finally thesolvent is distilled off under reduced pressure, whereupon methyl1-hydroxyindan-4-carboxylate is obtained. Recrystallization frometherpetroleum ether gives crystals melting at 65°-67° C.

EXAMPLES 2-(2)-2-(3)

In 100 ml. of water is dissolved 4.4 g. of sodium hydroxide, followed bythe addition of 17.6 g. of 1-oxoindan-4-carboxylic acid.

While the mixture is cooled in an ice-water bath, 1.89 g. of sodiumborohydride is added. The bath is removed and the mixture is stirred for3 hours, after which 5 ml. of acetone is added. After 1 hour, thereaction mixture is added to a solution of 70 g. of ice and 30 ml. ofconcentrated hydrochloric acid and the resultant crystals are collectedby filtration and recrystallized from acetone. The procedure gives1-hydroxyindan -4-carboxylic acid melting at 174°-176° C (decomp.).

By a similar manner to the above,1-hydroxy-1,2,3,4-tetrahydro-5-naphthoic acid is obtained from 19 g. of1,2,3,4-tetrahydro-1-oxo-naphthoic acid and 1.89 g. of sodiumborohydride. melting point: 160.5°-162.5° C (acetone).

EXAMPLE 2-(4)

To 200 ml. of ethanol is added 10.9 g. of ethyl1,2,3,4-tetrahydro-1-oxo-5-naphthoate and while the solution is stirredat room temperature, 950 mg. of sodium borohydride is added. The mixtureis stirred for 4 hours, after which 2 ml. of acetone is added. Themixture is further stirred for 30 minutes and, then, the solvent isdistilled off under reduced pressure. Following the addition of 30 ml.of 2N hydrochloric acid, the residue is extracted with ethyl ether. Theorganic layer is washed with water and dried over anhydrous magnesiumsulfate. The solvent is then distilled off under reduced pressure andthe oily residue is purified by column chromatography on silica gel(100g. silica gel; eluted with chloroform). The described procedure givesethyl 1-hydroxy-1,2,3,4-tetrahydro-5-naphthoate as an oily product.

Infrared absorption spectrum (neat)

1715 cm.sup.⁻¹ (carbony of ester)

Nuclear magnetic resonance spectrum (CDCl₃, 100 MHz)

δ : 1.36(3H, t, --CH₃), 4.31(2H, q, O--CH₂ --) 4.74(1H, t, C₁ --H).

EXAMPLE 3-(1)

To 30 ml. of benzene is added 5.35 g. of 1-hydroxyindan-4-carboxylicacid. Following the addition of 15 ml. of thionyl chloride, the mixtureis stirred for 3 hours. Then, the reaction mixture is concentrated todryness under reduced pressure and the resultant crystals arerecrystallized from benzene. The described procedure gives1-chloroindan-4-carboxylic acid melting at 135.5°-137.5° C.

EXAMPLE 3-(2)

In 6 ml. of chloroform is dissolved 5.7 g. of methyl1-hydroxyindan-4-carboxylate and, under cooling with ice, the solutionis stirred. Then, 3 ml. of thionyl chloride is added dropwise and, afterthe dropwise addition has been completed, the mixture is further stirredunder cooling with ice for one hour. Then, the solvent and the excessthionyl chloride are distilled off under reduced pressure. The residueobtained is purified by column chromatography on silica gel (500 g.silica gel; eluant: chloroform). The procedure gives methyl1-chloroindan-4-carboxylate as an oily product.

Infrared absorption spectrum (neat)

1720 cm⁻ ¹ (carbonyl of ester)

Nuclear magnetic resonance spectrum (CDCl₃, 60 MHz)

δ : 3.9 (3H, s, --CH₃), 5.41(1H, t, C₁ --H)

EXAMPLE 3-(3)

By a similar manner to Example 3-(2), ethyl1-chloro-1,2,3,4-tetrahydro-5-naphthoate is produced from ethyl1-hdyroxy-1,2,3,4-tetrahydronaphthoate and thionyl chloride.

Infrared absorption spectrum (neat)

1720 cm⁻ ¹ (carbonyl of ester)

Nuclear magnetic resonance spectrum (CDCl.sub. 3, 100 MHz)

δ : 1.36(3H, t--CH₃), 4.31(2H, q, O--CH₂ --), 5.29(1H, t, C, --H)

EXAMPLE 4-(1)

In 15 ml. of dimethylformamide is dissolved 1.97 g. of1-chloroindan-4-carboxylic acid, followed by the addition of 1.47 g. ofsodium cyanide. The mixture is stirred for 5 hours, after which 150 ml.of water and 10 ml. of concentrated hydrochloric acid are added. Theresultant crystals are collected by filtration and recrystallized frombenzene. The described procedure gives 1-cyanoindan-4-carboxylic acid,melting point: 206°-208° C.

EXAMPLE 4-(2)

In 80 ml. of dimethylsulfoxide is dissolved 15 g. of methyl1-chloroindan-4-carboxylate and the solution is stirred. Then, 5.3 g. ofsodium cyanide is added, followed by stirring for 8 hours. Following theaddition of 750 ml. of water, the reaction mixture is extracted withether. The extract is washed with a saturated aqueous solution of sodiumchloride and, then, dried. The solvent is distilled off under reducedpressure and the residue is purified by column chromatography on silicagel (500 g. silica gel; eluant: chloroform). The described proceduregives methyl 1-cyanoindan-4-carboxylate as crystals melting at76.5°-77.5° C.

EXAMPLE 4-(3)

In a mixture of 50 ml. of methanol and 50 ml. of water is dissolved 2.0g. of sodium hydroxide, and 6.0 g. of methyl 1-cyanoindan-4-carboxylateis added to the resultant solution. The mixture is heated in a waterbath maintained at about 50° C for about 20 minutes, after which time itis cooled, followed by the addition of 60 ml. of 1N hydrochloric acid.The resultant precipitate is extracted with chloroform and the extractis washed with water and dried. Then, the solvent is distilled off underreduced pressure, whereupon 1-cyanoindan-4-carboxylic acid is obtainedas crystals melting at 206°-208° C.

EXAMPLE 4-(4)

In 44 ml. of dimethylsulfoxide is dissolved 4.4 g. of ethyl1-chloro-1,2,3,4-tetrahydro-5-naphthoate, followed by the addition of 2g. of sodium cyanide. The mixture is stirred at 50° C for 3 hours andfollowing the addition of 450 ml. of 0.2N hydrochloric acid, the mixtureis extracted with ethyl ether. The organic layer is washed with waterand dried over anhydrous magnesium sulfate. The solvent is distilled offunder reduced pressure and the resultant oily residue is purified bycolumn chromatography on silica gel (100 g. silica gel; eluted withbenzene). The procedure gives ethyl1-cyano-1,2,3,4-tetrahydro-5-naphthoate as an oily product.

Infrared absorption spectrum (neat)

1720 cm⁻ ¹ (ester carbonyl)

2240 cm⁻ ¹ (nitrile)

Nuclear magnetic resonance spectrum (in CDCl₃, 100 MHz)

δ : 1.36(3H, t, --CH₃), 4.00(1H, t, C₁ --H), 4.33(2H, q, o--CH₂ --)

EXAMPLE 4-(5)

In 90 ml. of ethanol is dissolved 9.6 g. of ethyl1-cyano-1,2,3,4-tetrahydro-5-naphthoate and a solution of 2.5 g. ofsodium hydroxide in 90 ml. of water is added. The mixture is stirredunder heating at 50° C for 3 hours, after which the ethanol is distilledoff. Then, following the addition of 2N hydrochloric acid, the residueis extracted with chloroform. The organic layer is washed with water anddried over anhydrous magnesium sulfate. The solvent is distilled offunder reduced pressure and the crystalline residue is recrystallizedfrom benzene. The described procedure gives1-cyano-1,2,3,4-tetrahydro-5-naphthoic acid, melting point: 177°-179° C.

EXAMPLE 5-(1)

To 40 ml. of pyridine is added 19.2 g. of methyl1-hydroxyindan-4-carboxylate and, while the mixture is stirred at atemperature of not more than 10° C, 21 g. of p-toluenesulfonyl chlorideis added in small installments. After the addition has been completed,the reaction mixture is allowed to stand at a temperature not exceeding10° C for 6 hours. Then, following the addition of ice, the reactionmixture is extracted with ether. The extract is washed with water anddried. The solvent is then distilled off under reduced pressure and theresultant 4-carbomethoxy-1-indanyl p-toluenesulfonate is dissolved in100 ml. of dimethylsulfoxide, followed by stirring. Then, 5.5 g. ofsodium cyanide is added and the mixture is stirred at room temperaturefor 11 hours. Following the addition of 850 ml. of water, the reactionmixture is extracted with ether. The extract is washed with a saturatedaqueous solution of sodium chloride and, then, dried. The solvent isdistilled off under reduced pressure and the residue is purified bycolumn chromatography on silica gel (600 g. silica gel; eluant:chloroform). The described procedure gives methyl1-cyanoindan-4-carboxylate as crystals melting at 76°-77° C.

EXAMPLE 5-(2)

To 100 ml. of benzene is added 19.2 of1-hydroxy-1,2,3,4-tetrahydro-5-naphthoic acid, and following theaddition of 50 ml. of thionyl chloride, the solution is stirred for 8hours. The solvent and the excess thionyl chloride are distilled offunder reduced pressure and, then, 150 ml. of dimethylsulfoxide and 19.6g. of sodium cyanide are added, followed by stirring at 50° C for 6hours. Then, it is added to 1.5 l. of 1N hydrochloric acid and extractedwith ethyl ether. The organic layer is extracted with 800 ml. of 5%aqueous sodium hydroxide solution and after the addition of 100 ml. ofconcentrated hydrochloric acid, the solution is extracted withchloroform. The chloroform layer is washed with water and dried overanhydrous magnesium sulfate. The solvent is distilled off under reducedpressure and the crystalline residue is recrystallized from benzene. Theprocedure gives 1-cyano-1,2,3,4-tetrahydro-5-naphthoic acid, meltingpoint: 177°-179° C.

EXAMPLE 6-(1)

To dilute sulfuric acid, prepared from 54 ml. of water and 45 ml. ofconcentrated sulfuric acid, there is added 3 g. of4-benzoylindan-1-carbonitrile. The mixture is refluxed in a current ofnitrogen gas for 3 hours and a half. After cooling, the reaction mixtureis diluted with water and extracted with ether. The etheral layer isfurther extracted with a 5% aqueous solution of potassium carbonate andthe extract is washed with ether and rendered acidic with hydrochloricacid. The precipitate is extracted with chloroform and the extract iswashed with water and dried. The solvent is distilled off under reducedpressure, whereupon 4-benzoylindan-1-carboxylic acid is obtained.Recrystallization from benzene-cyclohexane (7:20) gives crystals meltingat 100°-102° C.

EXAMPLE 6-(2)

To dilute sulfuric acid, prepared from 27 ml. of water and 23 ml. ofconcentrated sulfuric acid, there is added 3 g. of4-(p-toluoyl)indan-1-carbonitrile. The mixture is refluxed in a currentof nitrogen gas for 3.5 hours. After cooling, the reaction mixture isdiluted with water and extracted with ether. The ethereal layer isextracted with a 5% aqueous solution of potassium carbonate and theextract is washed with water and rendered acidic with hydrochloric acid.The precipitate is extracted with chloroform and the extract is washedwith a saturated aqueous solution of sodium chloride and dried. Thesolvent is then distilled off under reduced pressure and the residue iscrystallized from benzene-cyclohexane (7:20). The described proceduregives 4-p-toluoylindan-1-carboxylic acid as crystals melting at128°-131° C.

EXAMPLE 6-(3)

In 500 ml. of methanol is dissolved 15 g. of4-benzoylindan-1-carbonitrile, followed by the addition of 150 ml. of a5 % aqueous solution of sodium hydroxide and 50 ml. of a 30 % aqueoussolution of hydrogen peroxide.

The mixture is heated at 60° C for 2 hours and cooled. The reactionmixture is rendered acidic by the addition of dilute hydrochloric acidand the resultant precipitate is extracted with ethyl acetate.

The extract is washed with water and dried. The solvent is distilled offunder reduced pressure and the residue is purified by columnchromatography on silica gel (500 g. silica gel; eluted withchloroform-acetone (7:3)). The described procedure gives4-benzoylindan-1-carboxamide as crystals melting at 164.5°-166° C.

EXAMPLES 6-(4)-6-(11)

By a similar manner to Example 6-(1), following compounds are produced.

    ______________________________________                                        Example Produced-compound                                                                              Starting compound                                    ______________________________________                                               4-(p-chlorobenzoyl)-                                                                           4-(p-chlorobenzoyl)-                                         indan-1-carboxylic                                                                             indan-1-carbonitrile                                  6-(4)  acid                                                                          melting point:                                                                138.5-139.5° C                                                         [benzene-cyclohexane                                                          (3:10)]                                                                       4-(p-bromobenzoyl)-                                                                            4-(p-bromobenzoyl)-                                          indan-1-carboxylic                                                                             indan-1-carbonitrile                                  6-(5)  acid                                                                          melting point:                                                                147.0-149.0° C                                                         [benzene-cyclohexane                                                          (1:1)]                                                                        4-(p-chloro-m-methyl-                                                                          4-(p-chloro-m-methyl-                                        benzoyl)indan-1- benzoyl)indan-1-                                      6-(6)  carboxylic acid  carbonitrile                                                 melting point:                                                                116-117° C[benzene-                                                    cyclohexane (3:20)]                                                           4-(p-t-butylbenzoyl)-                                                                          4-(p-t-butylbenzoyl)-                                        indan-1-carboxylic                                                                             indan-1-carbonitrile                                  6-(7)  acid                                                                          melting point:                                                                139-142° C [benzene-                                                   petroleum ether]                                                              4-(p-fluorobenzoyl)-                                                                           4-(p-fluorobenzoyl)-                                         indan-1-carboxylic                                                                             indan-1-carbonitrile                                  6-(8)  acid                                                                          melting point:                                                                109-110° C [benzene-                                                   cyclohexane (3:20)]                                                           5-benzoyl-1,2,3,4-                                                                             5-benzoyl-1,2,3,4-                                           tetrahydro-1-    tetrahydro-1-                                         6-(9)  naphthoic acid   naphthonitrile                                               melting point:                                                                164-165° C                                                             [benzene]                                                                     5-(p-toluoyl)-1,2,3,                                                                           5-(p-toluoyl)-1,2,3,                                         4-tetrahydro-1-  4-tetrahydro-1-                                        6-(10)                                                                              naphthoic acid   naphthonitrile                                               melting point:                                                                102-103° C                                                             [cyclohexane]                                                                 5-(p-chlorobenzoyl)-                                                                           5-(p-chlorobenzoyl)-                                         1,2,3,4-tetrahydro-1-                                                                          1,2,3,4-tetrahydro-                                    6-(11)                                                                              naphthoic acid   1-naphthonitrile                                             melting point:                                                                152.5-153° C                                                           [benzene-hexane]                                                       ______________________________________                                    

EXAMPLES 6-(12)-6-(15)

By a similar manner to Example 6-(3), following compounds are produced.

    ______________________________________                                        Example Produced-compound                                                                             Starting compound                                     ______________________________________                                               5-benzoyl-1,2,3,4-                                                                             5-benzoyl-1,2,3,4-                                           tetrahydro-1-    tetrahydro-1-                                         6-(12) naphthamide      naphthonitrile                                               melting point:                                                                145.5-147.5° C                                                         [cyclohexane]                                                                 5-(p-toluoyl)-1,2,                                                                             5-(p-toluoyl)-1,2,                                           3,4-tetrahydro-1-                                                                              3,4-tetrahydro-1-                                     6-(13) naphthamide      naphthonitrile                                               melting point:                                                                178-178.5° C                                                           [ethanol]                                                                     5-(p-chlorobenzoyl)-                                                                           5-(p-chlorobenzoyl)-                                         1,2,3,4-tetrahydro-                                                                            1,2,3,4-tetrahydro-1-                                 6-(14) 1-naphthamide    naphthonitrile                                               melting point:                                                                150.5-152.5° C                                                         (benzene)                                                                     4-(2,4,6-trimethyl-                                                                            4-(2,4,6-trimethyl-                                          benzoyl)indan-1- benzoyl)indan-1-                                      6-(15) carboxamide      carbonitrile                                                 melting point:                                                                195-198° C                                                             [ethanol]                                                              ______________________________________                                    

EXAMPLE 6-(16)

To 100 g. of polyphosphoric acid is added 2 g. of4-(p-chlorobenzoyl)indan-1-carbonitrile and the mixture is heated at150°-170° C for 2 hours.

The mixture is allowed to stand at room temperature overnight andfollowing the addition of water, it is extracted with ethyl acetate. Theextract is washed with 5 % aqueous sodium bicarbonate and water in thatorder and, then, dried over sodium sulfate.

The solvent is distilled off under reduced pressure and the solidresidue is recrystallized from 80 ml. of benzene. The procedure gives4-(p-chlorobenzoyl)indan-1-carboxamide as colorless crystals melting at159°-161° C. The crystal includes 1/6 mole equivalent of benzene.

EXAMPLE 6-(17)

To 2.3 g. of 4-(p-toluoyl)indan-1-carbonitrile is added 75 g. ofpolyphosphoric acid and the mixture is worked into a homogeneoussolution by heating on a water bath at 90° C for 30 minutes and, then,on an oil bath at 120°-130° C for 30 minutes. Following the addition ofwater to decompose the polyphosphoric acid, the reaction mixture isextracted with ethyl acetate. The extract is washed with water, 5 %aqueous sodium hydrogen carbonate and water in the order mentioned and,then, dried. It is, then, treated with activated carbon and concentratedunder reduced pressure. The resultant crystalline residue isrecrystallized from a mixture of ethanol and ethyl acetate. Thedescribed procedure gives 4-(p-toluoyl)indan-1-carboxamide as crystalsmelting at 188°-191° C.

EXAMPLE 6-(18)

To 3.0 g. of 4-(p-methoxybenzoyl)indan-1-carbonitrile is added 150 g. ofpolyphosphoric acid and the mixture is homogenized by heating in an oilbath at about 120° C. After 40 minutes of heating, the mixture isallowed to stand at room temperature overnight. The polyphosphoric acidis decomposed with 200 ml. of water, followed by extraction with ethylacetate. The extract is washed with water and dried. The solvent is thendistilled off under reduced pressure and the residue is recrystallizedfrom benzene. The described procedure gives4-(p-methoxybenzoyl)indan-1-carboxamide as crystals melting at 164°-166°C.

EXAMPLE 6-(19)

In 1 l. of a 10 % aqueous solution of hydrogen peroxide is dissolved 8g. of sodium hydroxide and, then, 20.1 g. of1-cyano-1,2,3,4-tetrahydro-5-naphthoic acid is added.

The mixture is stirred at 50° C for 20 hours, after which time 250 ml.of lN hydrochloric acid is added. The resultant crystals are collectedby filtration, washed with water and recrystallized from ethanol. Theprocedure gives 1-carbamoyl-1,2,3,4-tetrahydro-5-maphthoic acid, meltingpoint: 247°-249° C.

EXAMPLE 6-(20)

To 500 g. of polyphosphoric acid is added 22.4 g. of ethyl1-cyano-1,2,3,4-tetrahydro-5-naphthoate and the mixture is stirred at90°-100° C for 2 hours. Then, 1 l. of water is added, followed bycooling. The resultant crystals are collected by filtration, washed withwater and recrystallized from ethanol. The procedure gives ethyl1-carbamoyl-1,2,3,4-tetrahydro-5-naphthoate, melting point:159.5°-161.5° C.

EXAMPLE 6-(21)

To 60 % sulfuric acid is added 3.0 g. of4-(p-chlorobenzyl)indan-1-carbonitrile and the mixture is refluxed in acurrent of nitrogen gas for 2 hours. After cooling, water is added andthe mixture is extracted with ether. The ethereal solution is washedwith water and extracted with a 5 % aqueous solution of potassiumcarbonate. The extract is rendered acidic with hydrochloric acid and theresultant precipitate is extracted with chloroform. The chloroform layeris washed with water and dried. The solvent is distilled off underreduced pressure and the residue is crystallized from cyclohexane. Thedescribed procedure gives 4-p-chlorobenzyl)indan-1-carboxylic acid ascrystals melting at 127°-129° C.

EXAMPLE 6(22)-6-(24)

By a similar manner to Example 6-(21), the following compounds areproduced.

    ______________________________________                                        Example Produced-compound                                                                             Starting compound                                     ______________________________________                                               4-benzylindan-1- 4-benzylindan-1-                                             carboxylic acid  carbonitrile                                          6-(22) melting point:                                                                119.5-121° C                                                           [cyclohexane]                                                                 4-(p-methylbenzyl)-                                                                            4-(p-methylbenzyl)-                                          indan-1-carboxylic                                                                             indan-1-carbonitrile                                  6-(23) acid                                                                          melting point:                                                                124.5-126.5° C                                                         [cyclohexane]                                                                 4-(p-methoxybenzyl)-                                                                           4-(p-methoxybenzyl)-                                         indan-1-carboxylic                                                                             indan-1-carbonitrile                                  6-(24) acid                                                                          melting point:                                                                109.5-111.5° C                                                         [cyclohexane]                                                          ______________________________________                                    

EXAMPLE 7-(1)

In 100 ml. of dry tetrahydrofuran is dissolved 3.6 g. of 1,3-dithian andwhile the solution is chilled to -30° C in nitrogen gas streams andstirred, 10 ml. of a 20 % solution of n-butyl lithium in hexane is addeddropwise over a period of about 15 minutes. After the dropwise additionhas been completed, the solution is stirred at that temperature for 2hours and, then, at -50° C for 30 minutes. The solution is chilled againto -20° C and, under stirring, a solution of 7.1 g. of4-benzoylindan-1-one in 75 ml. of dry tetrahydrofuran is added dropwise.After the dropwise addition has been completed, the mixture is stirredat that temperature for 1 hour, after which it is allowed to stand at 0°C overnight. Then, the solvent is distilled off under reduced pressure.To the residue is added 15 ml. of dilute hydrochloric acid, followed byextraction with ether. The extract is washed with water and aqueoussodium chloride and, then, dried. The solvent is distilled off underreduced pressure and the residue is purified by column chromatography onsilica gel (500 g. silica gel, eluted with a 20:1 mixture of benzene andethyl acetate). The described procedure gives2-(4-benzoyl-1-hydroxy-1-indanyl)-1,3-dithian as an oily product. Theinfrared absorption spectrum (neat) of this product is in good agreementwith the assumed structure, absorbing at 1660 cm⁻ ¹ (ketone) and 3450cm⁻ ¹ (hydroxyl).

EXAMPLE 8-(1)

In 300 ml. of benzene is dissolved 1.4 g. of2-(4-benzoyl-1-hydroxy-1-indanyl)-1,3-dithian, followed by the additionof 600 mg. of p-toluenesulfonic acid. The mixture is refluxed for 3hours with removing the water azeotropically. After cooling, thesolution is washed with water, aqueous sodium bicarbonate and water inthe order mentioned and dried. The solvent is distilled off underreduced pressure, whereupon 2-(4-benzoyl-1-indanylidene)-1,3-dithian isobtained as an oily product. This product is used in the followingreaction without purification.

EXAMPLE 9-(1)

To 0.8 g. of 2-(4-benzoyl-1-indanylidene)-1,3-dithian are added 150 ml.of glacial acetic acid and 50 ml. of concentrated hydrochloric acid andthe mixture is refluxed for 3 hours, after which the solvent isdistilled off under reduced pressure. The residue is extracted withether.

The ethereal layer is washed with water and extracted with 5 % aqueoussodium carbonate. The extract is washed with ether and rendered acidicwith hydrochloric acid. The oily precipitate is extracted with ether.The extract is washed with water and aqueous solution of sodiumchloride, and dried. The solvent is distilled off under reduced pressureand the residue is crystallized from benzene-cyclohexane. The describedprocedure gives 4-benzyolindan-1-carboxylic acid as crystals melting at100°-102° C.

EXAMPLE 9-(2)

In 200 ml. of ethanol is dissolved 2.0 g. of the2-(4-benzoyl-1-indanylidene)-1,3-dithian obtained by the procedure ofExample 8-(1), and the solution is cooled with ice. Hydrogen chloridegas is bubbled through the solution for 15 minutes, after which it isallowed to stand under cooling with ice for 2 hours, then, at roomtemperature overnight. The excess hydrogen chloride and solvent aredistilled off under reduced pressure and, following the addition ofwater, the residue is extracted with ether. The extract is washed withwater and dried. The solvent is distilled off under reduced pressure andthe residue is purified by column chromatography on silica gel (200 g.silica gel; eluted with a 2.5 % solution of ethyl acetate in benzene).The described procedure gives ethyl 4-benzoylindan-1-carboxylate as anoil.

Infrared absorption spectrum (neat)

1720 cm⁻ ¹ (ester carbonyl)

1650 cm⁻ ¹ (ketone carbonyl)

EXAMPLE 10-(1)

In 100 ml. of dry tetrahydrofuran is dissolved 3.6 g. of 1,3-dithianand, under cooling at -30° C and stirring in a current of nitrogen gas,10 ml. of a 20 % solution of n-butyl lithium in hexane is added dropwiseover a period of about 20 minutes. After the dropwise addition has beencompleted, the mixture is stirred at the temperature mentioned for 2hours and, then, at -5° C for 30 minutes. The solution is chilled againto -20° C and, under stirring, a solution of 8.1 g. of4-(p-chlorobenzoyl)indan-1-one in 75 ml. of dry tetrahydrofuran is addeddropwise. After the drop-by-drop addition has been completed, themixture is stirred at the temperature mentioned for 1 hour and, then,allowed to stand at 0° C overnight. Then, the solvent is removed bydistillation under reduced pressure. Dilute hydrochloric acid is addedto the residue and the mixture is extracted with ether. The extract iswashed with water and aqueous solution of sodium chloride and, then,dried. The solvent is distilled off under reduced pressure and theresidue is subjected, without being purified, to the dehydrationreaction. Thus, the residue is dissolved in 350 ml. of benzene, and 600mg. of p-toluenesulfonic acid is added. The solution is refluxed for 3hours with removing the water azeotropically. After cooling, thesolution is washed with water, aqueous sodium bicarbonate and water inthe order mentioned. The solvent is distilled off under reduced pressureand the residue is hydrolyzed, without a purification procedure. Thus,to the residue are added 150 ml. of glacial acetic acid and 50 ml. ofconcentrated hydrochloric acid and the mixture is refluxed for 3 hours,after which the solvent is distilled off under reduced pressure. Theresidue is diluted with water and extracted with ether. The ethereallayer is washed with water and extracted with a 5 % aqueous solution ofsodium carbonate. The extract is washed with ether and rendered acidicwith hydrochloric acid. The resultant precipitate is extracted withchloroform and the extract is washed with water and dried. The solventis distilled off under reduced pressure and the residue is crystallizedfrom benzene-cyclohexane (3:10). The foregoing procedure gives4-(p-chlorobenzoyl)indan-1-carboxylic acid as crystals melting at137°-139° C.

EXAMPLES 10-(2)-10-(7)

By a similar manner to Example 10-(1), following compounds is produced.

    ______________________________________                                        Example Produced-compound                                                                             Starting compound                                     ______________________________________                                               4-(p-methylbenzoyl)-                                                                           1,3-dithian n-butyl                                          indan-1-carboxylic                                                                             lithium 4-(p-methyl-                                         acid             benzoyl)indan-1-one                                   10-(2) melting point:                                                                129.5-131.0° C                                                         [benzene-cyclohexane                                                          (8:25)]                                                                       4-(p-chloro-m-methyl-                                                                          1,3-dithian n-butyl                                          benzoyl)indan-1- lithium 4-(p-chloro-                                         carboxylic acid  m-methylbenzoyl)-                                     10-(3) melting point:   indan-1-one                                                  115.0-116.5° C                                                         [benzene-cyclohexane                                                          (3:20)]                                                                       5-benzoyl-1,2,3,4-                                                                             1,3-dithian n-butyl                                          tetrahydro-1-    lithium 5-benzoyl-1-                                  10-(4) naphthoic acid   tetralone                                                    melting point:                                                                164-165° C [benzene]                                                   5-(p-methylbenzoyl)-                                                                           1,3-dithian n-butyl                                          1,2,3,4-tetrahydro-                                                                            lithium 5-(p-methyl-                                  10-(5) 1-naphthoic acid benzoyl)-1-tetralone                                         melting point:                                                                102-103° C                                                             [cyclohexane]                                                                 5-(p-chlorobenzoyl)-                                                                           1,3-dithian n-butyl                                          1,2,3,4-tetrahydro-1-                                                                          lithium 5-(p-chloro-                                  10-(6) naphthoic acid   benzoyl)-1-tetralone                                         melting point:                                                                152.5-153.5° C                                                         [benzene-hexane]                                                              indan-1,4-dicarboy-                                                                            1,3-dithian n-butyl                                          ic acid          lithium methyl 1-                                     10-(7) melting point:   oxoindan-4-carboxylate                                       245.5-248° C                                                           [acetone]                                                              ______________________________________                                    

EXAMPLE 11-(1)

To 100 ml. of dry benzene are added 17.6 g. of 1-oxoindan-4-carboxylicacid and 22.9 g. of phosphorus pentachloride and, after stirring for 1.5hours, 40 g. of aluminum chloride is added. The mixture is stirred for 5hours, after which the product is poured into dilute hydrochloric acidand extracted with ether. The organic layer is dried and distilled freeof the solvent under reduced pressure. The crystalline residue isrecrystallized from cyclohexane. The described procedure gives4-benzoylindan-1-one which melts at 87°-89° C.

EXAMPLE 11-(2)

To 100 ml. of dry toluene are added 17.6 g. of 1-oxoindan-4-carboxylicacid and 22.9 g. of phosphorus pentachloride. The mixture is stirred atroom temperature for 1.5 hours, after which time 40 g. of aluminumchloride is added. The mixture is stirred overnight and, then, pouredinto 400 ml. of 3N hydrochloric acid, followed by extraction withbenzene. The organic layer is washed with water, aqueous sodiumhydroxide and water in the order mentioned and dried with anhydrousmagnesium sulfate. The solvent is distilled off under reduced pressureand the resultant crystalline residue is purified by columnchromatography on silica gel (200 g. silica gel; eluted withchloroform).

Finally, the eluate is recrystallized from acetone to give4-(p-toluoyl)indan-1-one, melting point: 105°-108° C.

EXAMPLES 11-(3)-11-(5)

By a similar manner to Example 11-(2), the following compounds areproduced.

    ______________________________________                                        Example Produced-compound                                                                             Starting compound                                     ______________________________________                                               4-(2,4,6-trimethyl-                                                                           1-oxoindan-4-carboxylic                                       benzoyl)indan-1-one                                                                           acid mesitylene                                        11-(3) melting point:                                                                159.5-161.5° C                                                         [benzene-hexane                                                               (1:1)]                                                                        5-benzoyl-3,4-  1,2,3,4-tetrahydro-                                           dihydro-1(2H)-  1-oxo-5-naphthoic                                      11-(4) naphthalenone   acid benzene                                                  melting point:                                                                72.5-73.5° C                                                           [cyclohexane]                                                                 5-(p-chlorobenzoyl)-                                                                          1,2,3,4-tetrahydro-                                           3,4-dihydro-1(2H)-                                                                            1-oxo-5-naphthoic                                      11-(5) naphthalenone   acid p-chlorobenzene                                          melting point:                                                                96-98° C                                                               [cyclohexane]                                                          ______________________________________                                    

EXAMPLE 11-(6)

To 200 ml. of chlorobenzene are added 17.6 g. of 1-oxoindan-4-carboxylicacid and 23 g. of phosphorus pentachloride. The mixture is stirred atroom temperature for 3 hours, after which time 40 g. of aluminumchloride is added. The mixture is stirred at about 65° C for 3 hours.After cooling, the mixture is poured into ice and hydrochloric acid,followed by extraction with chloroform. The extract is washed withwater, a saturated aqueous solution of sodium bicarbonate and water inthe order mentioned. After drying, the solvent is distilled off underreduced pressure and the residue is purified by column chromatography onsilica gel (200 g. silica gel; eluted with chloroform). Finally,recrystallization from a 20:5 mixture of benzene and hexane gives4-(p-chlorobenzoyl)indan-1-one as crystals melting at 144.5°-146° C.

EXAMPLES 11-(7)-11-(10)

By a similar manner to Example 11-(6), the following compounds areproduced.

    ______________________________________                                        Example Produced-compound                                                                             Starting compound                                     ______________________________________                                               4-(p-chloro-m-methyl-                                                                         1-oxoindan-4-                                                 benzoyl)indan-1-one                                                                           carboxylic acid                                        11-(7) melting point:  orthochlorotoluene                                            88-90° C [benzene-                                                     cyclohexane (3:20)]                                                           4-(p-fluorobenzoyl)-                                                                          1-oxoindan-4-                                                 indan-1-one     carboxylic acid                                        11-(8) melting point:  fluorobenzene                                                 93-94° C                                                               [chloroform]                                                                  4-(p-bromobenzoyl)-                                                                           1-oxoindan-4-                                                 indan-1-one     carboxylic acid                                        11-(9) melting point:  bromobenzene                                                  154-155° C                                                             [benzene-cyclohexane                                                          (1:1)]                                                                        5-(p-toluoyl)-3,4-                                                                            1,2,3,4-tetrahydro-                                           dihydro-1(2H)-  1-oxo-5-naphthoic                                      11-(10)                                                                              naphthalenone   acid phosphorus                                               melting point:  pentachloride                                                 86-87° C toluene                                                       [cyclohexane]                                                          ______________________________________                                    

EXAMPLE 11-(11)

To 5.5 g. of 1-cyanoindan-4-carboxylic acid is added 80 ml. of thionylchloride, and the mixture is allowed to stand at room temperature for 15hours. Then, the excess thionyl chloride is removed under reducedpressure. To the resultant 1-cyanoindan-4-carbonyl chloride are added.50 ml. of dry benzene and 8.0 g. of anhydrous aluminum chloride powderand the mixture is heated at about 60° C for 40 minutes. After cooling,the mixture is poured into ice-hydrochloric acid, followed by extractionwith ether. The extract is washed with 1N hydrochloric acid and asaturated aqueous solution of sodium chloride and, then, dried. Thesolvent is distilled off under reduced pressure and the residue ispurified by column chromatography on silica gel (400 g. of silica gel;eluted with chloroform).

The described procedure gives 4-benzoylindan-1-carbonitrile as an oilyproduct.

Infrared absorption spectrum (neat)

1660 cm⁻ ¹ (carbonyl)

2230 cm⁻ ¹ (nitrile)

Nuclear magnetic resonance spectrum (CDC_(l3), 60 MHz)

δ : 4.26 (1H, t, C₁ --H)

EXAMPLE 11-(12)

To 6.0 g. of 1-cyanoindan-4-carboxylic acid is added 96 ml. of thionylchloride and the mixture is allowed to stand at room temperature for 15hours. The excess thionyl chloride is removed under reduced pressure. To1-cyanoindan-4-carbonyl chloride, which is thus obtained as the residue,are added 50 ml. of anisole, 50 ml. of methylene chloride and 6.0 g. ofanhydrous aluminum chloride powder. The mixture is stirred at roomtemperature for 90 minutes. After cooling, the product is poured intoice-hydrochloric acid and extracted with ether. The extract is washedwith 1N hydrochloric acid and a saturated aqueous solution of sodiumchloride, followed by drying. The solvent is distilled under reducedpressure and the residue obtained is purified by chromatography on acolumn of silica gel (700 g. silica gel; eluted with chloroform). Theprocedure gives 4-(p-methoxybenzoyl)indan-1-carbonitrile as crystalsmelting at 109°-112° C.

EXAMPLE 11-(13)

To 6.0 g. of 1-cyanoindan-4-carboxylic acid is added 96 ml. of thionylchloride and the mixture is allowed to stand at room temperature for 14hours. The excess thionyl chloride is removed under reduced pressure. To1-cyanoindan-4-carbonylchloride, which is thus obtained as the residue,are added 50 ml. of toluene and 50 ml. of methylene chloride, followedby the addition of 6.0 g. of anhydrous aluminum chloride. The mixture isstirred at room temperature for 1 hour. After cooling, the reactionproduct is poured into ice-hydrochloric acid and extracted with ether.The extract is washed with 1N hydrochloric acid and a saturated aqueoussolution of sodium chloride, followed by drying. The solvent isdistilled off under reduced pressure and the residue is purified bycolumn chromatography on silica gel (500 g. silica gel; eluted withchloroform). The procedure gives 4-(p-toluoyl)indan-1-carbonitrile as anoily product.

Infrared absorption spectrum (neat)

1655 cm⁻ ¹ (carbonyl)

2230 cm⁻ ¹ (nitrile)

Nuclear magnetic resonance spectrum (CDCl₃ , 6MHz)

67 : 4.2 (1H, t, C₁ --H), 2.45(3H, s, --CH₃)

EXAMPLE 11-(14)

To 6.0 g. of 1-cyanoindan-4-carboxylic acid are added 20 ml. ofchloroform and 80 ml. of thionyl chloride and the mixture is allowed tostand at room temperature for 15 hours. The excess thionyl chloride andchloroform are distilled off under reduced pressure. To1-cyanoindan-4-carbonyl chloride, which is thus obtained as thedistillation residue, is added 100 ml. of chlorobenzene, followed bystirring under cooling with ice. Then, 6.0 g. of anhydrous aluminumchloride powder is added and the temperature is gradually increased toabout 80° C, at which temperature the reaction mixture is stirred for2.5 hours. After cooling, ice-hydrochloric acid is added, followed byextraction with ether. The extract is washed with water and dried. Then,the solvent is distilled off under reduced pressure and the residueobtained is purified by column chromatography on silica gel (700 g.silica gel; eluant: chloroform). The described procedure gives4-(p-chlorobenzoyl)indan-1-carbonitrile as an oily product.

Infrared absorption spectrum (neat)

1660 cm⁻ ¹ (carbonyl)

2230 cm⁻ ¹ (nitrile)

Nuclear magnetic resonance spectrum (CDCl₃, 60 MHz)

δ: 4.17 (1H, t, C₁ --H)

EXAMPLES 11(15)-11-(17)

By a similar manner to Example 11-(11) the following compounds areproduced.

    ______________________________________                                        Example Produced-compound                                                                             Starting compound                                     ______________________________________                                               5-benzoyl-1,2,3,4-                                                                            1-cyano-1,2,3,4-                                              tetrahydro-1-   tetrahydro-5-naphthoic                                 11-(15)                                                                              naphthonitrile  acid                                                          melting point:  thionyl chloride                                              91.5-93.5° C                                                                           benzene                                                       [n-hexane]                                                                    5-(p-toluoyl)-  1-cyano-1,2,3,4-                                              1,2,3,4-tetra-  tetrahydro-5-                                          11-(16)                                                                              hydro-1-naphtho-                                                                              naphthoic acid                                                nitrile         thionyl chloride                                              melting point:  toluene                                                       72-73° C [n-hexane]                                                    5-(p-chlorobenzoyl)-                                                                          1-cyano-1,2,3,4-                                              1,2,3,4-tetrahydro-                                                                           tetrahydro-5-                                          11-(17)                                                                              1-naphthonitrile                                                                              naphthoic acid                                                melting point:  thionyl chloride                                              97-99° C [n-hexane]                                                                    chlorobenzene                                          ______________________________________                                    

EXAMPLE 11-(18)

To 4.0 g. of 1-cyanoindan-4-carboxylic acid are added 60 ml. ofchloroform and 60 ml. of thionyl chloride and the mixture is allowed tostand at room temperature for 2 days.

The excess thionyl chloride and the chloroform are distilled off underreduced pressure and 30 g. of t-butylbenzene added to the resultant acidchloride. Then, under cooling with ice and stirring, 10 g. of aluminumchloride is added. The mixture is stirred at room temperature for 30minutes, at 50° C for another 30 minutes and, then, at room temperaturefor 3 hours.

Ice is added to the reaction mixture, followed by extraction withbenzene. The extract is washed with water and dried. Then, the solventis distilled off under reduced pressure and the residue is purified bycolumn chromatography (600 g. silica gel; eluted with a 100:0.5 mixtureof benzene and ethyl acetate). The described procedure gives1-cyano-4-(p-t-butylbenzoyl)indan.

Infrared absorption spectrum (neat)

2250 cm⁻ ¹ (nitrile)

1660 cm⁻ ¹ (ketone)

EXAMPLE 11-(19)

To 130 ml. of thionyl chloride is added 10.2 g. of1-carbamoylindan-4-carboxylic acid and the mixture is allowed to standat room temperature for 14 hours.

The excess thionyl chloride is distilled off under reduced pressure. Tothe 1-carbamoylindan-4-carbonyl chloride obtained as the distillationresidue are added 50 ml. of benzene, 50 ml. of carbon disulfide and 10.0g. of anhydrous aluminum chloride powder, and the mixture is stirred atabout 40° C for 30 minutes. After cooling, ice-hydrochloric acid isadded, followed by extraction with ethyl acetate. The extract is washedwith 1N hydrochloric acid and a saturated aqueous solution of sodiumchloride, followed by drying. The solvent is distilled off under reducedpressure and the residue is purified by column chromatography on silicagel (500 g. silica gel; eluted with chloroform-acetone (7:3)).

The described procedure gives 4-benzoylindan-1-carboxamide as crystalsmelting at 163.5°-165.5° C.

EXAMPLES 11-(20)-11-(22)

By a similar manner to Example 11-(19), the following compounds areproduced.

    ______________________________________                                        Example Produced-compound                                                                             Starting compound                                     ______________________________________                                               5-benzoyl-1,2,3,4-                                                                             1-carbamoyl-1,2,3,4-                                         tetrahydro-1-    tetrahydro-5-naphthoic                                11-(20)                                                                              naphthamide      acid                                                         melting point:   benzene                                                      145.5-147.5°C                                                          [cyclohexane]                                                                 5-(p-toluoyl)-1,2,                                                                             1-carbamoyl-1,2,3,4-                                         3,4-tetrahydro-1-                                                                              tetrahydro-5-                                         11-(21)                                                                              naphthamide      naphthoic acid                                               melting point    toluene                                                      178-178.5° C                                                           [ethanol]                                                                     5-(p-chlorobenzoyl)-                                                                           1-carbamoyl-1,2,3,4-                                         1,2,3,4-tetrahydro-                                                                            tetrahydro-5-                                         11-(22)                                                                              1-naphthamide    naphthoic acid                                               melting point:   chlorobenzene                                                150.5-152.2° C                                                         [benzene]                                                              ______________________________________                                    

EXAMPLE 12-(1)

To 120 ml. of carbon disulfide is added 54 g. of anhydrous aluminumchloride powder on an ice bath, followed by the dropwise addition of asolution of 11.4 g. of ethyl indan-1-carboxylate in 60 ml. of carbondisulfide. The mixture is stirred for 10 minutes, after which a solutionof 42 g. of benzoyl chloride in 60 ml. of carbon disulfide is addeddropwise. After the dropwise addition has been completed, thetemperature is gradually increased and the solution is stirred on refluxfor 3 hours and thirty minutes to complete the reaction. Ice andhydrochloric acid are added to the reaction mixture followed byextraction with ether. The extract is washed with 1N hydrochloric acid,water, a saturated aqueous solution of sodium bicarbonate and asaturated aqueous solution of sodium chloride in the order mentionedand, then, dried over anhydrous sodium sulfate. The solvent is thendistilled off under reduced pressure and the residue iscolumn-chromatographed on silica gel (conditions: 2 Kg. of silica gel;eluant solvent-benzene containing 2.5 % of ethyl acetate). Thefirst-emerging fractions rich in ethyl 4-benzoylindan-1-carboxylate arepooled separate from the ensuing fractions rich in ethyl6-benzoylindan-1-carboxylate. The former fractions are further purifiedby rechromatography on a column of silica gel, whereby ethyl4-benzoylindan-1-carboxylate is obtained as an oily product.

Infrared absorption spectrum (neat)

1720 cm⁻ ¹ (ester carbonyl)

1650 cm⁻ ¹ (ketone carbonyl)

EXAMPLES 12-(2)-12-(5)

By a similar manner to Example 12-(1), the following compounds areproduced.

    ______________________________________                                        Example Produced-compound                                                                             Starting compound                                     ______________________________________                                               4-(p-toluoyl)indan-                                                                            indan-1-carboxamide                                          1-carboxamide    p-toluoyl chloride                                    12-(2) melting point:                                                                188-191° C ethanol-                                                    ethyl acetate]                                                                5-benzoyl-1,2,3,4-                                                                             1,2,3,4-tetrahydro-                                          tetrahydro-1-    1-naphthamide                                         12-(3) naphthamide      benzoyl chloride                                             melting point:                                                                145.5-147.5                                                                   [cyclohexane]                                                                 5-(p-toluoyl-1,2,3,                                                                            1,2,3,4-tetrahydro-                                          4-tetrahydro-1-  1-naphthamide                                         12-(4) naphthamide      p-toluoyl chloride                                           melting point:                                                                178-178.5° C                                                           [ethanol]                                                                     5-(p-chlorobenzoyl)-                                                                           1,2,3,4-tetrahydro-                                          1,2,3,4-tetrahydro-                                                                            1-naphthamide                                         12-(5) 1-naphthamide    p-chlorobenzoyl                                              melting point:   chloride                                                     150.5-152.5° C                                                         [benzene]                                                              ______________________________________                                    

EXAMPLE 13-(1)

In 100 ml. of acetic acid is dissolved 11.1 g. of 4-benzyl indan-1-one,followed by the addition of 13.4 g. of chromic acid and 2.5 ml. ofconcentrated sulfuric acid. The mixture is stirred at room temperaturefor 2 hours, after which it is poured into 4 l. of water. After 200 g.of anhydrous potassium carbonate is added, the mixture is extracted withchloroform. The organic layer is washed with water and dried overanhydrous magnesium sulfate. The solvent is distilled off under reducedpressure and the oily residue is purified by column chromatography onsilica gel with chloroform as the eluent and, then, recrystallized fromcyclohexane. The procedure gives 4-benzoylindan-1-one melting at 87°-89°C.

EXAMPLES 13-(2)14 ---(3)

By a similar manner to Example 13-(1), the following compounds areproduced.

    ______________________________________                                        Example Produced-compound                                                                             Starting compound                                     ______________________________________                                               4-(p-chlorobenzoyl)-                                                                           4-(p-chlorobenzyl)-                                          indan-1-one      indan-1-one                                           13-(2) melting point:   chromic anhydride                                            145-146° C                                                             [benzene-cyclohexane                                                          (1:1)]                                                                        4-(p-toluoyl)indan-                                                                            4-(p-methylbenzyl)-                                   13-(3) 1-one            indan-1-one                                                  [acetone]        chromic anhydride                                     ______________________________________                                    

EXAMPLE 13-(4)

To 60 ml. of dioxane are added 8.0 g. of4-(p-methoxybenzyl)indan-1-carbonitrile and 2.8 g. of selenium dioxideand the mixture is refluxed for 12 hours. After cooling, water is added,followed by extraction with chloroform. The extract is washed with waterand dried. Then, the solvent is distilled off under reduced pressure andthe residue is purified by column chromatography (500 g. silica gel;eluted with chloroform). The crude crystals thus obtaind arerecrystallized from benzene. The procedure gives4-(p-methoxybenzoyl)indan-1-carbonitrile as crystals melting at115.5°-117.5° C.

EXAMPLE 13-(5)

In 100 ml. of acetic acid is dissolved 6.7 g. of5-benzyl-1,2,3,4-tetrahydro-1-naphthoic acid and, under cooling withice, 3.4 g. of chromic anhydride is added. The mixture is stirred well.After stirring overnight, the reaction mixture is poured over 500 g. ofice and extracted with chloroform.

The chloroform layer is washed with water and dried over anhydrousmagnesium sulfate. The solvent is distilled off under reduced pressureand the residual oily liquid is chromatographed on a column of silicagel equilibrated with oxalic acid with chloroform as the eluant and,then, recrystallized from benzene. The procedure gives5-benzoyl-1,2,3,4-tetrahydro-1-naphthoic acid, melting point: 164°-165°C.

EXAMPLE 13-(6)

In 200 ml. of 1N aqueous hydroxide is dissolved 14 g. of5-(p-methylbenzyl)-1,2,3,4-tetrahydro-1-naphthoic acid, and a solutionof 26 g. of potassium permanganate in 800 ml. of water is addeddropwise. After stirring overnight, the reaction mixture is renderedacidic by the addition of concentrated sulfuric acid, followed by theaddition of sodium bisulfite. The mixture is extracted with chloroformand the chloroform layer is washed with water and dried over anhydrousmagnesium sulfate. The solvent is distilled off under reduced pressureand the oily residue is purified by column chromatography on silica gelequilibrated with oxalic acid and, then, recrystallized fromcyclohexane. The described procedure gives5-(p-toluoyl)-1,2,3,4-tetrahydro-1-naphthoic acid, melting point:102°-103° C.

EXAMPLE 13-(7)

To 200 ml. of ethyl ether is added 15 g. of5-(p-chlorobenzyl)-1,2,3,4-tetrahydro-1-naphthoic acid, and a solutionof 5 g. of sodium dichromate in 24 ml. of 6N sulfuric acid is addeddropwise. After stirring overnight, 100 ml. of water is added and theethereal layer is further washed with water and dried over anhydrousmagnesium sulfate. The solvent is distilled off under reduced pressureand the oily residue is purified by column chromatography on silica gelequilibrated with oxalic acid with chloroform as the eluent and, thenrecrystallized from benzene. The described procedure gives5-(p-chlorobenzoyl)-1,2,3,4-tetrahydro-1-naphthoic acid, melting point:152.5°-153.5° C.

EXAMPLE 13-(8)

To 100 ml. of acetic acid is added 6.6 g. of5-benzyl-1,2,3,4-tetrahydro-1-naphthamide and, under cooling with ice,3.4 g. of chromic anhydride is added. The mixture is stirred well. Afterstirring overnight, the reaction mixture is poured over 500 g. of iceand the resultant crystals are collected by filtration. This issubjected to column chromatography on silica gel using chloroform as theeluent and the eluate is recrystallized from cyclohexane. The proceduregives 5-benzoyl-1,2,3,4-tetrahydro-1-naphthamide, melting point:145.5°-147.5° C.

EXAMPLE 13-(9)

To 60 ml. of dioxane are added 6.3 g. of 4-benzylindan-1-carboxylic acidand 2.8 g. of selenium dioxide and the mixture is refluxed for 12 hours.After cooling, water and chloroform are added and the insolubles arefiltered off. The filtrate is extracted with chloroform and thechloroform layer is extracted with 5 % aqueous potassium carbonate. Theextract is decolorized with activated carbon and rendered acidic withhydrochloride acid. The precipitate is extracted with chloroform and theextract is washed with water and dried. The solvent is distilled offunder reduced pressure and the residue is crystallized from a 20:7solvent mixture of cyclohexane and benzene. The described proceduregives 4-benzoylindan-1-carboxylic acid as crystals melting at 100°-102°C.

EXAMPLES 13-(10)-13-(12)

By a similar manner to Example 13-(6), the following compounds areproduced.

    ______________________________________                                        Example Produced compound                                                                             Starting compound                                     ______________________________________                                               4-(p-toluoyl)indan-                                                                            4-(p-methylbenzyl)-                                          1-carboxylic acid                                                                              indan-1-carboxylic                                    13-(10)                                                                              melting point:   acid                                                         130-131.5° C [benzene-                                                 cyclohexane (8:25)]                                                           4-(p-chlorobenzoyl)-                                                                           4-(p-chlorobenzyl)-                                          indan-1-carboxylic                                                                             indan-1-carboxylic                                    13-(11)                                                                              acid             acid                                                         melting point:                                                                137-139° C [benzene-                                                   cyclohexane (3:10)]                                                           4-(p-methoxybenzoyl)-                                                                          4-(p-methoxybenzyl)-                                         indan-1-carboxylic                                                                             indan-1-carboxylic                                    13-(12)                                                                              acid             acid                                                         melting point:                                                                136.5-138° C [benzene]                                          ______________________________________                                    

EXAMPLE 13-(13)

To 150 ml. of acetone is added 12.5 g. of 6-benzylindan-1-carboxamide,followed by the dropwise addition of a solution of 5 g. of sodiumdichromate in 24 ml. of 6N sulfuric acid. After the addition has beencompleted, the mixture is stirred overnight. Then 200 ml. of water isadded and the acetone is distilled off under reduced pressure. Theresidue is extracted with ethyl acetate. The extract is washed withwater and dried, followed by removal of the solvent by distillationunder reduced pressure. The residue is purified by column chromatography(500 g. of silica gel; eluted with a 7:3 solvent mixture of chloroformand acetone) and the resultant crude crystals are recrystallized frombenzene. The procedure gives 6-benzoylindan-1-carboxamide as crystalsmelting at 195°-197° C.

EXAMPLE 13-(14)

In 100 ml. of acetic acid is dissolved 7.3 g. of ethyl4-benzylindan-1-carboxylate and, under cooling with ice, 3.4 g. ofchromic anhydride is added. After the mixture is stirred overnight, thereaction mixture is poured over 500 g. of ice and extracted withchloroform. The extract is washed with water and dried. The solvent isdistilled off under reduced pressure and the residue is purified bycolumn chromatography (700 g. silica gel; eluted with a 40:1 mixture ofbenzene and ethyl acetate). The procedure gives ethyl4-benzoylindan-1-carboxylate as an oily product.

Infrared absorption spectrum (neat)

1720 cm.sup.⁻¹ (ester carbonyl)

1650 cm.sup.⁻¹ (ketone carbonyl)

EXAMPLE 14-(1)

Sodium ethoxide, prepared from 1.1 g. of sodium metal, is dissolved in amixture of 24 ml. of dry ethanol and 48 ml. of dry dimethoxyethane and,under cooling with ice-water and stirring, the resultant solution isadded dropwise to a 120 ml. of dry dimethoxyethane solution dissolving9.5 g. of 4-benzoylindan-1-one and 9.4 g. of N-(p-toluenesulfonylmethyl)isonitrile over a period of 20 minutes. After the dropwise addition hasbeen completed, the mixture is further stirred at the same temperaturefor 30 minutes and at room temperature for 3.5 hours. Following theaddition of water, the reaction mixture is extracted with ether and theextract is washed with water and dried. The solvent is distilled offunder reduced pressure and the residue is purified by columnchromatography on silica gel (1 Kg. of silica gel; eluant: benzene-ethylacetate (50:1)). The described procedure gives4-benzoylindan-1-carbonitrile as an oily product.

Infrared absorption spectrum (neat)

1660 cm.sup.⁻¹ (carbonyl)

2230 cm.sup.⁻¹ (nitrile)

Nuclear magnetic resonance spectrum (CDCl₃, 60 MHz)

δ : 4.26 (1H, t, C₁ --H)

EXAMPLES 14-(2) -14-(10 )

By a similar manner to Example 14-(1), the following compounds areobtained.

    ______________________________________                                        Example Produced-compound                                                                             Starting compound                                     ______________________________________                                               4-(p-toluoyl)indan-                                                                           4-(p-toluoyl)indan-                                    14-(2) 1-cabonitrile   1-one                                                         IR 1665 cm.sup..sup.-1 -carbonyl,                                                             N-(p-toluenesulfonyl-                                         2225 cm.sup.-1(nitrile)                                                                       methyl)isonitrile                                             4-(p-fluorobenzoyl)-                                                                          4-(p-fluorobenzoyl)-                                          indan-1-carbonitrile                                                                          indan-1-one                                            14-(3) IR 1655 cm.sup..sup.-1                                                                        N-(p-toluenesulfonyl-                                         (carbonyl),2230 cm.sup..sup.-1                                                                methyl)isonitrile                                             (nitrile)                                                                     4-(p-chlorobenzoyl)-                                                                          4-(p-chlorobenzoyl)-                                          indan-1-carbonitrile                                                                          indan-1-one                                            14-(4) melting point:  N-(p-toluenesulfonyl-                                         116-118° C [benzene-                                                                   methyl)isonitrile                                             cyclohexane(1:10)]                                                            4-(p-bromobenzoyl)-                                                                           4-(p-bromobenzoyl)-                                           indan-1-carbonitrile                                                                          indan-1-one                                            14-(5) melting point:  N-(p-toluenesulfonyl-                                         114-116° C [benzene-                                                                   methyl)isonitrile                                             hexane-cyclohexane                                                            (3:20:20)]                                                                    4-(p-chloro-m-  4-(p-chloro-m-methyl-                                         methylbenzoyl)indan-                                                                          benzoyl)indan-1-one                                           1-carbonitrile  N-(p-toluenesulfonyl-                                  14-(6) oily product    methyl)isonitrile                                             IR 1660 cm.sup..sup.-1                                                        (carbonyl), 2240 cm.sup..sup.-1                                               (nitrile)                                                                     4-(2,4,6-tri-methyl-                                                                          4-(2,4,6-trimethyl-                                           benzoyl)indan-1-                                                                              benzoyl)indan-1-one                                    14-(7) carbonitrile    N-(p-toluenesulfonyl-                                         melting point:  methyl)isonitrile                                             133.5-135° C [cyclo-                                                   hexane-hexane]                                                                5-benzoyl-1,2,3,4-                                                                            5-benzoyl-3,4-dihydro-                                        tetrahydro-1-   1(2H)naphthalenone                                     14-(8) naphthonitrile  N-(p-toluenesulfonyl-                                         melting point:  methyl)isonitrile                                             91.5-93.5° C [hexane]                                                  5-(p-toluoyl)-1,2,3,                                                                          5-(p-toluoyl)-3,4-                                            4-tetrahydro-1- dihydro-1(2H)-                                         14-(9) naphthonitrile  naphthalenone                                                 melting point:  N-(p-toluenesulfonyl-                                         72-73° C [hexane]                                                                      methyl)isonitrile                                             5-(p-chlorobenzoyl)-                                                                          5-(p-chlorobenzoyl)-                                          1,2,3,4-tetrahydro-                                                                           3,4-dihydro-1(2H)-                                     14-(10)                                                                              1-naphthonitrile                                                                              naphthalenone                                                 melting point:  N-(p-toluenesulfonyl-                                         97-99° C [hexane]                                                                      methyl)isonitrile                                      ______________________________________                                    

EXAMPLE 14-(11)

Sodium ethoxide, prepared from 1.4 g. of sodium metal, is dissolved in amixture of 30 ml. of dry ethanol and 60 ml. of dry dimethoxyethane and,under cooling with ice and stirring, the resultant solution is addeddropwise to a 150 ml. of dry dimethoxyethane solution dissolving 8.2 g.of ethyl 1-oxoindan-4-carboxylate and 12 g. ofN-(p-toluenesulfonylmethyl)isonitrile over a period of 35 minutes. Afterthe dropwise addition has been completed, the mixture is stirred at thesame temperature for 35 minutes and, then, at room temperature for 5.5hours. Following the addition of water, the reaction mixture isextracted with ether and the extract is washed with water and dried. Thesolvent is distilled off under reduced pressure and the residue ispurified by column chromatography on silica gel (1 Kg. of silica gel;eluant: benzene-ethyl acetate (50:1)). Recrystallization fromcyclohexane gives ethyl 1-cyanoindan-4-carboxylate as crystals meltingat 93°-95.5° C.

EXAMPLE 14-(12)

By a similar manner to Example 14-(11), ethyl ester of1-cyano-1,2,3,4,-tetrahydro-5-naphthoic acid is produced as an oilysubstance from ethyl ester of 1,2,3,4-tetrahydro-1-oxo-5-naphthoic acidand N-(p-toluenesulfonylmethyl)isonitrile.

Infrared absorption spectrum(neat)

1720 cm¹¹⁶ 1 (carbonyl), 2240 cm¹¹⁶ 1 (nitrile)

Nuclear magnetic resonance spectrum (CDCl₃, 100 MHz)

δ : 1.36(3H, t, --CH₃), 4.00(1H, t, C₁ --H), 4.33)2H, q, O--CH₂ --)

EXAMPLE 14-(13)

In 80 ml. of dry dimethoxyethane are dissolved 5.2 g. of4-(p-chlorobenzyl)indan-1-one and 6 g. ofN-(p-toluenesulfonylmethyl)isonitrile and while the solution is stirredunder cooling with ice, a solution of 0.72 g. of sodium metal in asolvent mixture of 20 ml. of dry ethanol and 40 ml. of drydimethoxyethane is added dropwise over a period of about 30 minutes.After the drop-by-drop addition has been completed, the mixture isstirred under cooling with ice for 1 hour and, then, at room temperaturefor 3 hours. After the reaction has been completed, 800 ml. of dilutehydrochloric acid are added, followed by extraction with ether. Theextract is washed with aqueous sodium chloride and dried. The solvent isdistilled off under reduced pressure and the residue is purified bycolumn chromatography (600 g. of silica gel; elution with a 100:1mixture of benzene and ethyl acetate). The described procedure gives4-(p-chlorobenzyl)indan-1-carbonitrile as an oily product.

Infrared absorption spectrum (neat)

2250 cm.sup.⁻¹ (nitrile)

Nuclear magnetic resonance spectrum (CDCl₃ solution, 60 MHz)

δ : 2.0-3.0 (4H, m, --CH₂ --CH₂ --)

δ : 3.85 (2h, s, Ar--CH₂ --Ar)

δ : 4.02 (1H, t, >CH--CN)

δ : 6.8-7.4 (7h, m, aromatic protons)

EXAMPLES 14-(14)-14 -(16)

By a similar manner to Example 14-(13), the following compounds areproduced.

    ______________________________________                                        Example Produced compound                                                                             Starting compound                                     ______________________________________                                               4-benzylindan-1- 4-benzylindan-1-                                             carbonitrile     one                                                   14-(14)                                                                              melting point:                                                                43-44.5° C                                                             [n-hexane]                                                                    4-(p-methylbenzyl)-                                                                            4-(p-methylbenzyl)-                                          indan-1-carbonitrile                                                                           indan-1-one                                           14-(15)                                                                              melting point:                                                                60-62° C                                                               [n-hexane]                                                                    4-(p-methoxybenzyl)-                                                                           4-(p-methoxybenzyl)-                                         indan-1-carbonitrile                                                                           indan-1-one                                           14-(16)                                                                              NMR(CDCl.sub.3, 100MHz)                                                       δ:2.2-3.0(4H,m,--CH 2--                                                  CH.sub.2--), 3.63(3H,s,                                                       --OCH.sub.3), 3.80(2H,s,                                                      φ--CH.sub.2--A4), 3.96 (1H,                                               t,>CH--Cl)6.7-7.3                                                             (7H,m,aromatic)                                                       ______________________________________                                    

EXAMPLE 15-81)

In 50 ml. of ether is dissolved 2.7 g. of 4-benzoylindan-1-carboxylicacid and, then, an ethereal solution of diazomethane is added until theyellow color of the solution has not disappeared. The solution is thenallowed to stand for 30 minutes, after which the excess diazomethane andthe ether are distilled off. The methyl 4-benzoylindan-1-carboxylatethus obtained as the distillation residue is dissolved in 50 ml. ofdimethylsulfoxide and under stirring, the solution is added dropwise to100 ml. of dimethylsulfoxide containing 1.5 g. of sodium hydride over aperiod of 15 minutes.

After the dropwise addition has been completed, the mixture is furtherstirred for 2.5 hours and, then, a solution of 15.0 g. of methyl iodidein 30 ml. of dimethylsulfoxide is added dropwise over a period of 30minutes. After the dropwise addition has been completed, the mixture isfurther stirred for 2.0 hours. The mixture is rendered acidic withdilute hydrochloric acid and, then, extracted with ether. The extract iswashed with water and dried. Then, the solvent is distilled off underreduced pressure and the residue is purified by column chromatography onsilica gel(300 g. silica gel; eluted with a 40:1 mixture of benzene andethyl acetate). The described procedure gives methyl4-benzoyl-1-methylindan-1-carboxylate as an oily product.

Elemental analysis C₁₉ H₁₈ O₃ :

Calcd. C, 77.53; H, 6.16.

Found C, 77.34; H, 6.10.

EXAMPLE 15-(2)

By a similar manner to Example 15-(1), the following compounds areproduced.

    ______________________________________                                        Example  Produced-compound                                                                              Starting compound                                   ______________________________________                                                4-benzoyl-1-methyl-                                                                             4-benzoylindan-1-                                           indan-1-carboxamide                                                                             carboxamide                                         15-(2)  melting point:109-110                                                                           methyl iodide                                               ° C [benzene-hexane                                                    (1:1)]                                                                ______________________________________                                    

EXAMPLE 15-(3)

In 50 ml. of ether is dissolved 3.0 g. of4-(p-chlorobenzoyl)indan-1-carboxylic acid and the esterification iscarried out by adding an ethereal solution of diazomethane.

The excess diazomethane and the ether are distilled off under reducedpressure, The resultant methyl 4-(p-chlorobenzoyl)indan-1-carboxylate isdissolved in 50 ml. of dimethylsulfoxide and under stirring, thesolution is added dropwise to 100 ml. of dimethylsulfoxide containing1.5 g. of sodium hydride over a period of 15 minutes. After the dropwiseaddition has been completed, the mixture is stirred for 3.0 hours and,then, a solution of 15.0 g. of methyl iodide in 30 ml. ofdimethylsulfoxide is added dropwise over 25 minutes. After the dropwiseaddition has been completed, the mixture is further stirred for 2.0hours.

It is then rendered acidic with dilute hydrochloric acid and extractedwith ether. The extract is washed with water and dried. The solvent isthen distilled off under reduced pressure and the residue is purified bycolumn chromatography (300 g. silica gel; eluted with a 40:1 mixture ofbenzene and ethyl acetate). The procedure gives methyl4-(p-chlorobenzoyl)-1-methylindan-1-carboxylate as an oily product. Thisproduct is dissolved in a solvent mixture of 35 ml. of ethanol and 35ml. water and, then, 1.6 g. of potassium hydroxide is added. The mixtureis refluxed for 2 hours, after which the ethanol is distilled off.Following the addition of 100 ml. of water, the residue is washed withether. The water layer is rendered acidic with hydrochloric acid and theresultant precipitate is extracted with chloroform. The extract iswashed with water and dried. The solvent is then distilled off underreduced pressure and the residue is crystallized from a 7:20 mixture ofbenzene and hexane. The procedure gives4-(p-chlorobenzoyl)-1-methylindan-1-carboxylic acid as colorlesscrystals melting at 146.5°-149.5° C.

EXAMPLE 15-(4)

In 50 ml. of ether is dissolved 2.8 g. of4-(p-toluoyl)indan-1-carboxylic acid and the esterification is carriedout by adding an ethereal solution of diazomethane.

The excess diazomethane and the ether are distilled off under reducedpressure. The resultant methyl 4-(p-toluoyl)indan-1-carboxylate isdissolved in 50 ml. of dimethylsulfoxide and under stirring, thesolution is added dropwise to 100 ml. of dimethylsulfoxide containing1.0 g. of sodium hydride over a period of 15 minutes. After the dropwiseaddition has been completed, the mixture is stirred for 2.5 hours and,then, a solution of 15.0 g. methyl iodide in 30 ml. dimethylsulfoxide isadded drop by drop over a period of 25 minutes. After the dropwiseaddition has been completed, the mixture is further stirred for 2.5hours. It is then rendered acidic with dilute hydrochloric acid andextracted with ether. The extract is washed with water and dried.Finally the solvent is distilled off under reduced pressure and theresidue is purified by column chromatography (300 g. silica gel; elutedwith a 40:1 mixture of benzene and ethyl acetate). The procedure givesmethyl 4-(p-toluoyl)-1-methylindan-1-carboxylate as an oily product.This product is dissolved in a solvent mixture of 35 ml. ethanol and 35ml. water and, then, 1.5 g. of potassium hydroxide is added. The mixtureis refluxed for 2 hours, after which time the ethanol is distilled offunder reduced pressure. Following the addition of 100 ml. of water, theresidue is washed with ether. The water layer is rendered acidic withhydrochloric acid and the precipitate is extracted with chloroform. Theextract is washed with water and dried.

Finally the solvent is distilled off under reduced pressure and theresidue is crystallized from a 1:4 mixture of benzene and hexane. Thedescribed procedure gives 4-(p-toluoyl)-1-methylindan-1-carboxylic acidas crystals melting at 99°-101° C.

EXAMPLE 16-(1)

In 35 ml. of ethanol is dissolved 1.5 g. of ethyl4-benzoylindan-1-caboxylate, followed by the addition of a solution of800 mg. of potassium hydroxide in 35 ml. of water. The mixture is heatedon reflux for 2 hours, after which it is concentrated under reducedpressure.

The residue is dissolved in 300 ml. of water and the water layer iswashed with ether and made acidic with hydrochloric acid. Theprecipitate is extracted with chloroform and the organic layer is washedwith water and dried over anhydrous sodium sulfate. Then, the solvent isdistilled off, which leaves an oil of 4-benzoylindan-1-carboxylic acid.This product is dissolved in a 7:20 solvent mixture of benzene andcyclohexane and the solution is allowed to stand, whereupon crystalsseparate out gradually, melting point:101.5°-103° C.

EXAMPLE 16-(2)

To 500 ml. of concentrated hydrochloric acid is added 15.9 g. of4-benzoylindan-1-carboxamide and the mixture is refluxed for 5 hours.After cooling, the solution is extracted with chloroform and thechloroform layer is washed with water and extracted with a 1N aqueoussolution of sodium hydroxide. The extract is decolorized with activatedcarbon and rendered acidic by the addition of hydrochloric acid,followed by extraction with chloroform. The extract is washed with waterand a saturated aqueous solution of sodium chloride and, then, dried.

The solvent is distilled off under reduced pressure and the residue iscrystallized from benzene-cyclohexane (7:20). The described proceduregives 4-benzoylindan-1-carboxylic acid as crystals melting at100.5°-102° C.

EXAMPLE 16-(3)

To 13.3 g. of 4-benzoylindan-1-carboxylic acid is added 50 ml. ofthionyl chloride and the mixture is left standing at room temperatureovernight. Then, the excess thionyl chloride is distilled off underreduced pressure. Ether is added to the residue and, then, ammonia gasis bubbled through the reaction mixture. The resultant precipitate isrecovered by filtration, washed with water and dried. Recrystallizationfrom benzene gives 4-benzoylindan-1-carboxamide as crystals melting at164°-166° C.

EXAMPLE 16-(4)

To 250 ml. of ethanol is added 20 ml. of concentrated sulfuric acid,followed by the addition of 13.3 g. of 4-benzoylindan-1-carboxylic acid.The mixture is refluxed for 5.5 hours. After cooling, the ethanol isdistilled off under reduced pressure and water is added to the residue,followed by extraction with ether. The ethereal layer is washed with a 5% aqueous solution of sodium hydroxide and a saturated aqueous solutionof sodium chloride and, then, dried. The solvent is distilled off underreduced pressure and the residue is purified by column chromatography onsilica gel (eluted with chloroform). The described procedure gives ethyl4-benzoylindan-1-carboxylate as an oily product.

Infrared absorption spectrum (neat)

1720 cm.sup.⁻¹ (ester carbonyl)

1650 cm.sup.⁻¹ (ketone carbonyl)

EXAMPLE 16-(5)

To 3 g. of 4-benzoylindan-1-carboxylic acid are added 25 ml. ofchloroform and 25 ml. of thionyl chloride. The mixture is allowed tostand overnight and, then, the excess thionyl chloride and the solventare distilled off under reduced pressure. To the acid chloride thusobtained is added 50 ml. of benzene. Then, 50 ml. of water, 7.0 g. ofhydroxylamine hydrochloride and 4.0 g. of sodium hydroxide are furtheradded. The mixture is stirred at room temperature for 4 hours. Followingthe addition of water, the reaction mixture is extracted with ethylacetate and the extract is washed with water and dried. The solvent isthen distilled off under reduced pressure and the residue isrecrystallized from benzene. The procedure givesN-hydroxy-4-benzoylindan-1-carboxamide as crystals melting at159.5°-160.5° C.

EXAMPLE 16-(6)

To 3.0 g. of 4-benzoylindan-1-carboxylic acid are added 25 ml. ofchloroform and 25 ml. of thionyl chloride. The mixture is allowed tostand at room temperature overnight and, then, the excess thionylchloride and the solvent are distilled off under reduced pressure. Tothe acid chloride thus obtained are added 50 ml. of benzene and 10 ml.of aqueous methylamine solution (40 %). The mixture is stirred at roomtemperature for 4 hours, after which water is added, followed byextraction with ethyl acetate. The extract is washed with water anddried. Finally the solvent is distilled off under reduced pressure andthe residue is crystallized from a mixture of benzene and ether. Theprocedure gives N-methyl-4-benzoylindan-1-carboxamide as crystalsmelting at 145°-146.5° C.

EXAMPLE 16-(7)

To 3.0 g. of 4-benzoylindan-1-carboxylic acid are added 25 ml. ofchloroform and 25 ml. of thionyl chloride. The mixture is allowed tostand at room temperature overnight and the excess thionyl chloride andthe solvent are distilled off under reduced pressure. To the acidchloride thus obtained are added 50 ml. of benzene and 5 ml. ofmorpholine, followed by stirring at room temperature overnight.

Then, water is added and the mixture is extracted with benzene. Theextract is washed with 1N hydrochloric acid and, then, with water anddried. The solvent is distilled off under reduced pressure and theresidue is purified by column chromatography (300 g. silica gel, elutedwith a 100:3 mixture of chloroform and acetone). The procedure gives4-benzoylindan-1-carboxyl morpholide as an oily product.

Infrared absorption spectrum (neat)

1655 cm.sup.⁻¹ (amide and ketone)

EXAMPLE 16-(8)

In a solution of 450 g. of sodium hydroxide in 20 ml. of water, there isdissolved 3.35 g. of 4-benzoylindan-1-carboxylic acid and the insolublesare filtered off. To the filtrate is added a solution of 950 mg. ofaluminum chloride hexahydrate in 100 ml. of water and the mixture isstirred for 3 hours. The resultant crystals are collected by filtration,washed with water, dried and washed with ether. The procedure givesaluminum tris(4-benzoylindan-1-carboxylate) is obtained as crystalsmelting at 225°-230° C.

EXAMPLE 16-(9)

In 50 ml. of ether is dissolved 2.66 g. of 4-benzoylindan-1-carboxylicacid. To this is added an ethanolic solution of sodium ethoxide preparedfrom 230 mg. of sodium metal and 10 ml. of ethanol. The mixture isallowed to stand for 20 minutes, after which time the solvent isdistilled off under reduced pressure.

The resultant powder is washed with acetone, whereuponsodium-4-benzoylindan-1-carboxylate is obtained as a powder melting at238°-240° C (in a sealed tube).

EXAMPLE 16-(10)

To 14.0 g. of 4-(p-toluoyl)indan-1-carboxamide is added 500 ml. ofconcentrated hydrochloric acid and the mixture is refluxed for 3.5hours. After cooling, the mixture is extracted with chloroform and thechloroform layer is washed with water and extracted with a 5 % aqueoussolution of potassium carbonate. The extract is decolorized withactivated carbon and rendered acidic with hydrochloric acid. Theprecipitate is extracted with chloroform. The extract is washed withwater and dried. The solvent is distilled off under reduced pressure andthe residue is crystallized from an 8:25 mixture of benzene andcyclohexane. The described procedure gives4-(p-toluoyl)indan-1-carboxylic acid as crystals melting at 130°-131.5°C.

EXAMPLES 16-(11) -16-(14)

By a similar manner to Example 16-(2), the following compounds areproduced. pg,90

    ______________________________________                                        Example Produced-compound                                                                             Starting compound                                     ______________________________________                                               4-(p-methoxybenzoyl)-                                                                          4-(p-methoxybenzoyl)-                                        indan-1-carboxylic                                                                             indan-1-carboxamide                                   16-(11)                                                                              acid                                                                          melting point:                                                                137.5-138.5° C                                                         [benzene)]                                                                    5-benzoyl-1,2,3,4-                                                                             5-benzoyl-1,2,3,4-                                           tetrahydro-1-    tetrahydro-1-                                         16-(12)                                                                              naphthoic acid   naphthamide                                                  melting point:                                                                164-165° C [benzen]                                                    5-(p-chlorobenzoyl)-                                                                           5-(p-chlorobenzoyl)-                                         1,2,3,4-tetrahydro-                                                                            1,2,3,4-tetrahydro-                                   16-(13)                                                                              1-naphthoic acid 1-naphthamide                                                melting point:                                                                152.5-153.5° C                                                         [benzene-hexane]                                                              4-(2,4,6-trimethyl-                                                                            4-(2,4,6-trimethyl-                                          benzoyl)indan-1- benzoyl)indan-1-                                      16-(14)                                                                              carboxylic acid  carboxamide                                                  melting point:                                                                191.5-193° C [benzene-                                                 cyclohexane (1:1)]                                                     ______________________________________                                    

EXAMPLE 16-(14)

To 500 ml. of concentrated hydrochloric acid is added 17.6 g. of 5-(p-toluoyl)-1,2,3,4-tetrahydro-1-naphthamide and the mixture isrefluxed for 5 hours. After cooling, it is extracted with chloroform andthe chloroform layer is washed with water and extracted with 1N sodiumhydroxide. The extract is decolorized with activated carbon, renderedacidic with hydrochloric acid and extracted with chloroform. Thechloroform layer is washed with water and dried. The solvent isdistilled off under reduced pressure and the crystalline residue isrecrystallized from benzene. The procedure gives5-(p-toluoyl)-1,2,3,4-tetrahydro-1-naphthoic acid, melting point:102°-103° C

EXAMPLE 17-(1)

To 60 ml. of acetone are added 3.2 g. of 4benzoylindan-1-carboxylic acidand 1.70 g. of cinchonidine and the mixture is shaken to dissolve. Thesolution is allowed to stand at room temperature overnight and theresultant crystals are recovered by filtration and recrystallized twicefrom acetone. The procedure gives l-4-benzoylindan-1-carboxylic acidcinchonidine salt as colorless crystals melting at 189°-192° C, [α]_(D)²² - 132.2° (c=1, CHCl₃).

This product is dissolved in chloroform and the solution is shaken twicewith portions of dilute hydrochloric acid to remove the cinchonidine.

The chloroform layer is washed with water and dried over magnesiumsulfate. The solvent is distilled off under reduced pressure. Theprocedure gives l-4-benzoylindan-1-carboxylic acid as a colorless oil,[α]_(D) ²² - 66.4° (c=1, MeOH).

The mother liquor after harvest of the first crop of crystals isconcentrated under reduced pressure and the residue is shaken with 1.7g. of cinchonidine and 120 ml. of acetonitrile under stirring andheating, after which the mixture is allowed to stand at room temperatureovernight. The resultant crystals are collected by filtration andrecrystallized three times from acetonitrile. The described proceduregives d-4-benzoylindan-1-carboxylic acid cinchonidine salt as colorlesscrystals melting at 180°-183° C, [α]_(D) ²² 11.2° (c=1, CHCl₃). Thisproduct is dissolved in chloroform and the solution is shaken twice withportion of hydrochloric acid to remove the cinchonidine. The chloroformlayer is washed with water and dried over magnesium sulfate. Finally,the solvent is distilled off under reduced pressure to obtaind-4-benzoylindan-1-carboxylic acid as a colorless oil, [α]_(D) ²² 66.4°(c=1, MeOH).

EXAMPLE 17-(2)

To 100 ml. of acetone are added 3.1 g. of4-(p-chlorobenzoyl)indan-1-carboxylic acid and 1.5 g. of cinchonine andthe mixture is warmed to dissolve. Then, with the addition of a smallamount of activated carbon, the solution is filtered. The filtrate isallowed to stand at room temperature overnight and, then, at 0°-5° C foranother night. The crystals formed are recovered by filtration andrecrystallized from acetonitrile. The described procedure givesl-4-(p-chlorobenzoyl)indan-1-carboxylic acid cinchonine salt ascolorless crystals, melting point: 193°-196° C, [α]_(D) ²³ 33.6° (c=1,CHCl₃).

The above product is dissolved in chloroform and the solution is shakentwice with portion of dilute hydrochloric acid to remove the cinchonine.The chloroform layer is washed with water and dried over magnesiumsulfate. The solvent is distilled off under reduced pressure, andcyclohexane is added to the residue. The resultant crystals arecollected by filtration and recrystallized from a 1:4 mixture of benzeneand cyclohexane. The procedure givesl-4-(p-chlorobenzoyl)indan-1-carboxylic acid as colorless crystalsmelting at 121°-122° C. [α]_(D) ²⁴ - 66.9° (c=1, MeOH)

EXAMPLE 17-(3)

In 100 ml. of acetone are dissolved 3.1 g. of4-(p-chlorobenzoyl)indan-1-carboxylic acid and 1.5 g. cinchonine underheating and, with the addition of a small amount of activated carbon,the solution is filtered. The filtrate is allowed to stand at roomtemperature overnight and, then, at 0°-5° again overnight. The resultantcrystals are filtered off. The filtrate is concentrated under reducedpressure and the residue is dissolved in 50 ml. of acetonitrile. Thesolution is allowed to stand for a week and the crystals formed arefiltered off. The filtrate is concentrated under reduced pressure andthe residue is dissolved in 150 ml. of chloroform. The solution iswashed twice with dilute hydrochloric acid and once with water, anddried by the addition of magnesium sulfate. The solvent is distilled offunder reduced pressure and the residue is dissolved in 80 ml. ofacetonitrile, followed by the addition of 0.6 g. of l-α-phenethylamine.The mixture is allowed to stand overnight and the resultant crystals arecollected by filtration and recrystallized five times from acetonitrile.

The described procedure gives d-4-(p-chlorobenzoyl)indan-1-carboxylicacid l-α-phenethylamine salt as colorless crystals melting at 148°-150°C. [α]_(D) ²⁴ 62.2° (c=1, CHCl₃).

This product is dissolved in 150 ml. of chloroform and the solution iswashed twice with dilute hydrochloric acid and once with water and driedby the addition of magnesium sulfate. The solvent is distilled off underreduced pressure and cyclohexane is added to the residue. The resultantcrystals are collected by filtration and recrystallized twice from a 1:4mixture of benzene and cyclohexane. The procedure givesd-4-(p-chlorobenzoyl)indan-carboxylic acid as colorless crystals meltingat 121°-122° C, [α]_(D) ²⁴ 65.0° (c=1, MeOH).

What is claimed is:
 1. A compound of the formula ##STR7## wherein R¹ isphenyl which is unsubstituted or substituted by lower alkyl having 1 to4 carbon atoms, lower alkoxy having 1 to 4 carbon atoms, halogen, mono-or di-alkylamino having 1 to 3 carbon atoms, acetylamino, orpropionylamino and n is 1 or
 2. 2. A compound claimed in claim 1 whereinn is
 1. 3. A compound claimed in claim 1 wherein n is
 2. 4. A compundclaimed in claim 1 wherein R¹ is phenyl which is unsubstituted.
 5. Acompound claimed in claim 1 wherein R¹ is phenyl which is substituted bylower alkyl having 1 to 4 carbon atoms, lower alkoxy having 1 to 4carbon atoms, halogen, mono- or di-alkylamino having 1 to 3 carbonatoms, acetylamino, or propionylamino.
 6. A compound claimed in claim 1wherein the compound is 4-benzoylindan-1-carboxamide.
 7. A compoundclaimed in claim 1 wherein the compound is4-(p-chlorobenzoyl)indan-1-carboxamide.
 8. A compound claimed in claim 1wherein the compound is 4-(p-toluoyl)indan-1-carboxamide.
 9. A compoundclaimed in claim 1 wherein the compound is4-(p-methoxybenzoyl)indan-1-carboxamide.